The underlying processes of both depression and FM can be characterized by the lifetime course in an individual person. These processes can be organized by the three “P”s of predisposing, precipitating, and perpetuating factors. Considerable evidence suggests that genetic and environmental factors predispose
individuals to develop depression or FM. Indeed, a fundamental property of the multiple genetic associations with depression is not that these genes cause depression but rather that they increase the risk of developing depression in response to a precipitating event [9
]. The considerable evidence for increased vulnerability to depression includes genes involved in the function of serotonin, catecholamines, monoamines, CRF, glutamate, and brain-derived neurotrophic factor [9
]. The evidence suggests that these genes result in an intermediate phenotype that increases the general risk of a psychiatric disorder precipitated by an environmental stressor or other triggering event [9
]. A similar concept has been proposed for FM in which both genetic factors and environmental events predispose individuals to develop FM in response to a subsequent precipitating event. Genetic factors in FM are implicated by familial prevalence [6
]. Converging evidence suggests that a polymorphism in the serotonin transporter (5-HTT) gene, implicated in MDD, may also be implicated in FM [19
]. This genetic influence, the established influence of environment, and gene/environmental interactions may all predispose individuals to develop FM and depression. Many of the precipitating events described below, such as physical trauma or sexual abuse, also likely contribute to a predisposed state.
Raphael et al. [18
] have provided elegant evidence for the separate and joint predisposition to develop FM and MDD. In a community-based sample, they recruited individuals with both, either, or no MDD and FM, essentially filling 4 cells of a 2 × 2 table of FM presence (y/n) for one dimension and MDD presence (y/n) for the other dimension. These four cells defined subject categories, and the data of interest were collected from all available adult first-degree relatives of these subjects. Unlike previous studies that used reports of the primary subjects for data on relatives, this study actually interviewed the relatives. The results support a familial aggregation of FM and MDD. In comparison to a baseline rate of MDD of 28.7% in relatives of subjects without either MDD or FM, the rate of MDD in relatives was 39.0% in subjects with MDD and 37.3% in subjects with FM. Having both FM and MDD increased the rate of MDD in relatives to 45.5%. Expressed as odds ratios (ORs) in comparison to the groups that did not have either MDD or FM, the FM and MDD were similar with ORs of 1.47 and 1.56, and the combination of both FM and MDD increased the ORs of family MDD to 2.02.
The results of Raphael et al. [18
] were interpreted as support for FM as a depression spectrum disorder. Interestingly, the linkage for FM and MDD was not found for FM and any mood disorder excluding MDD. These results suggest a familial, likely genetic, linkage in the predisposition for acquiring FM and MDD and also suggest that depressive symptoms without MDD can be in reaction to the presence of FM and not due to a linked common mechanism.
Once predisposed to develop FM or depression, these syndromes can be precipitated
by events ranging from injury to psychosocial stressors [21
]. Cited physical examples include physical trauma, illness, infections such as HIV, surgery, and autoimmune disease and motor vehicle accidents [7
]. Psychosocial stressors range from catastrophic events such as war to sexual abuse and other forms of emotional stress and trauma [7
]. Physical and psychosocial workplace events can also trigger these syndromes. Harkness et al. [24
] documented precipitating physical workplace, events such as heavy lifting and repetitive motion, and psychosocial factors such as monotonous work and low social support.
Once triggered, both depression and FM involve a number of similar physiological mechanisms that likely perpetuate these disorders. It is well known that the acute response to stress, mobilizing the organism to deal with potentially life-threatening events, is beneficial if it remains acute. If abnormally prolonged, the disruption of normal bodily processes can lead to a number of disease states. The acute stress response, detailed in numerous reports, involves activation of the hypothalamic-pituitary-adrenal (HPA) axis which is coupled to the autonomic and limbic systems. Activation of the HPA system involves a chain of events. Corticotrophin-releasing hormone (CRH) is secreted by the hypothalamus, which results in pituitary secretion of ACTH. This CRH effect is synergistically augmented by hypothalamic secretion of argininevasopressin (AVP). Increased ACTH in turn stimulates adrenal secretion of cortisol. Cortisol is a potent glucocorticoid that activates cytoplasmic receptors throughout the body to ultimately mobilize action and inhibit vegetative processes such as reproduction and growth. The glucocorticoids also provide negative feedback regulation of the HPA axis via multiple pathways acting on the hypothalamus and pituitary. These effects of the HPA axis activation are integrated with the locus ceruleus-norepinephrine system (LCNE) that activates brain systems involved in affect and anticipation, precipitation, propagation and termination of stress-related activity and activation of pain [25
The pathophysiology of both stress-induced depression and fibromyalgia has been described in terms of the deleterious consequences of an acute stress response that persists far beyond a normal duration, failing to “reset” after the stressor is removed or terminated. The results have been characterized by the effects on cortisol secretion, which interact with neurotransmitter systems and regulation of fatigue, affect, and pain, linking fibromyalgia and the subsets of depression described below.