Acta neurol. belg., 2006, 106, 149-156 Abstract There is increasing evidence that stress and depres- sion may play a crucial role in the aetiology and patho- physiology of fibromyalgia (FM). We first review recent studies on the possible role of life stress, including child- hood trauma, in FM. Subsequently we focus on clinical and aetio-pathogenetic links between stress, depression and pain. We put forward the hypothesis that chronic stress / depression may contribute to a dysregulation of neuro-endocrine, immune and central pain mechanisms in FM. Finally, we discuss some future directions, including the use of new conceptual models, research topics and strategies, as well as potential implications from recent studies in affective disorders for the treat- ment of FM. Key words : Depression ; childhood trauma ; chronic fatigue syndrome ; fibromyalgia ; life events ; neuro- biology ; stress ; treatment. Introduction Fibromyalgia (FM) is a syndrome characterized by medically unexplained, widespread muscu- loskeletal pain, hyperalgesia and/or allodynia, physical and mental fatigue and effort intolerance, non-restorative sleep, mood disturbance as well as other functional (e.g. gastrointestinal) complaints (Mease et al. 2005). The syndrome shows substan- tial symptomatic and diagnostic overlap with chronic fatigue syndrome (CFS) (Clauw and Chrousos 1997 ; Sullivan et al. 2002 ; Meeus et al. in press) and other functional somatic syndromes such as irritable bowel syndrome (IBS) (Wessely et al. 1999 ; Aggarwal et al. 2006). In the following paragraphs, we discuss (1) the precipitating, predisposing and perpetuating role of physical and psychosocial stressors in FM ; (2) evi- dence concerning clinical and aetio-pathogenetic links between stress, depression and FM ; (3) a pathophysiological hypothesis on the role of chron- ic stress and depression in dysregulating neuroen- docrine, immune and central pain mechanisms in FM ; (4) important methodological issues with regard to stress and depression research in FM ; (5) lessons from recent therapeutic studies in affec- tive disorders that may also inform FM treatment ; and (6) new conceptual models, topics and strate- gies for future research in this domain. Life stress and FM PRECIPITATING STRESSORS Although clinical experience and retrospective studies suggest that the onset of FM is frequently associated with various types of negative life events (Anderberg et al. 2000 ; Poyhia et al. 2001) and personally-relevant daily hassles (Van Houdenhove et al. 2002), prospective studies could only partial- ly confirm these findings (Raphael et al. 2002 ; Willliams et al. 2003 ; Kivimäki et al. 2004). Whether traumatic stressors or posttraumatic stress disorder (PTSD) may precipitate FM still remains a controversial issue, although evidence for the frequent co-occurrence of PTSD and FM is increasing, in adult patients (Sherman et al. 2000 ; White et al. 2000 ; Cohen et al. 2002a ; Roy-Burne et al. 2004 ; Ciccone et al. 2005 ; Arguelles et al. 2006), as well as in children (Seng et al. 2005). The nature of the relationship remains unclear, but according to some authors, depression might be a mediating factor (Raphael et al. 2004a). PREDISPOSING STRESSORS Numerous retrospective case-control studies have shown that traumatic experiences (neglect, maltreatment or abuse) during childhood are more frequently reported by FM patients than by med- ically ill or healthy controls (for a review see e.g. Imbierowicz and Egle 2003 ; Davis et al. 2005 ; Van Houdenhove et al. in press). Although these findings suggest that early life stress may play a predisposing role in the aetio-pathogenesis of FM, such studies should be interpreted with caution due to confounding factors such as recall bias, response bias and health-care seeking bias (Hardt et al. 2004 ; Raphael 2005). Traumatic experiences may augment vulnera- bility to FM via multiple and interacting mecha- nisms, notably psychophysiological mechanisms Review articles Stress, depression and fibromyalgia B. VAN HOUDENHOVE 1 and P. LUYTEN 2 1 Dept of Liaison Psychiatry, University Hospital Gasthuisberg, Leuven, Belgium ; 2 Department of Psychology, K.U.Leuven, Leuven, Belgium ————