Date

June 2007

Document Type

Dissertation

Degree Name

Ph.D.

Institution

Oregon Health & Science University

Abstract

Background: Fibromyalgia (FM) is a common, costly and debilitating chronic pain syndrome diagnosed in nearly 10 million Americans, 90% of whom are women. Conservative estimates place direct and indirect costs of FM at $15.9 billion annually. By definition, people with FM have chronic widespread pain and specified tender point areas at tendon-muscle junctions. Other symptoms associated with FM include disrupted sleep, fatigue, cognitive dysfunction, and mood disorders, mostly depression. The lifetime prevalence of depression in fibromyalgia patients is approximately 60% and suicide is the leading cause of premature mortality. Five distinct subtypes of major depressive disorder have been identified in depressed populations, with atypical and melancholic depressive episodes accounting for 45%-60% of all depression subtypes. There is increasing evidence that supports a biological link between depressive illness and chronic pain. Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is one of the most consistent findings in depression research and has been reported in a subset of FM patients. HPA axis dysfunction is the best-defined physiological abnormality in patients with depressive disorders, especially those with melancholic depressive episodes (MOE). It has been hypothesized that the two main depression subtypes, melancholic depressive episodes and atypical depressive episodes (ADE), exist in FM as well and that they exhibit differing levels of HPA axis activation as measured by the dexamethasone suppression test (DST): MOE having increased HPA activation and ADE having reduced HPA activation. In addition, work from our group has reported hypothalamic pituitary growth hormone (HPGH) axis with low plasma IGF-1 levels --a measure of 48-hour growth hormone (GH) secretion-- in about one third of persons with FM. Further experiments have shown that the reduced GH secretion in FM patients is a result of increased hypothalamic somatostatin tone, which inhibits growth hormone secretion. MOE is associated with increased secretion of corticotropin releasing hormone (CRH), which in turn stimulates the secretion of somatostatin. Thus, it is logical to assume that FM patients with MOE may have reduced levels of GH secretion as evidenced by low plasma IGF-1 levels. It is important to determine if ADE and MOE follow the same clinical and biochemical patterns in a depressed FM population as has been documented in depressed non-FM populations. Research has shown ADE has a preferential response to monoamine oxidase inhibitors (MAOis) and MOE has a preferential response to CRH antagonists. If it is found that ADE is more prominent in an FM with concurrent Major Depressive Disorder (MOD) population than MOE, this knowledge will support the need to consider more specific prescribing practices based on the need to activate versus attenuate the HPA axis. Objectives: The purpose of the study was to directly test the hypothesis that MOD subtypes exist in FM and can be identified via clinical characteristics and biochemical assays. In addition, growth hormone production was evaluated for differences among diagnostic groups. Design: The study was a cross-sectional descriptive study with three groups of patients: (1) non-depressed fibromyalgia patients (FM no MOD), (2) fibromyalgia patients with melancholic depressive episodes (FM/MDE), and (3) fibromyalgia patients with atypical depressive episodes (FM/ADE). Setting and Subjects: Invitation letters were mailed to 1582 FM patients selected via a computer generated random numbers table from a tertiary care fibromyalgia clinic data base of over 8,000 FM patients in the Pacific Northwest. Over-sampling for zip codes known to have high ethnic diversity was completed to maximize minority inclusion. The study included men and women between the ages of 20 to 90. Measurements: The diagnosis of MOD, MOE, and ADE were evaluated by a semi-structured clinical interview using the DSM-IV-TR diagnostic criteria for MOD plus the ADE and MOE subtype criteria. Independent variables of FM, depression, and pain severity; sleep quality; quality of life; and impact of FM on ability to function were also measured using standard instruments with established validity and reliability. HPA axis function as evidenced by plasma cortisol levels was assessed using the DST in all subjects (n=65) and a combined DEX suppression/CRH stimulation test in a subset of subjects (n=19). HPGH axis function was measured via standard laboratory assays of plasma IGF-1. Analysis: Descriptive statistics were used to characterize demographics (age, gender, race, ethnicity, education, disability status, and marital status) and clinical variables (FM, depression and pain severity; sleep quality; quality of life; and impact of FM on ability to function). Chi square tests and analysis of variance (ANOVA) with Bonferonni and Games-Howell post-hoc tests were used to determine if significant differences existed among diagnostic groups on demographic and clinical characteristics, pre-CRH stimulation highest mean plasma cortisol levels, post-CRH stimulation peak plasma cortisol levels, and plasma IGF-1 levels. Results: A higher occurrence of ADE (n=40, 52.6%) versus MOE (n= 27, 35.5%) was found in the sample. No significant differences existed among the three groups on baseline demographic characteristics except for the expected predominance of females to males. Significant differences were found on all clinical characteristics among diagnostic groups except for number of tender points and body mass index. In the DST group, there was a trend in the expected direction for plasma cortisol levels, but no significant differences were found among the diagnostic groups. In the DEX/CRH group, mean peak plasma cortisol levels in the FM no MOD and FM/ADE groups did not significantly differ from each other. However, significant differences did exist between the FM/ADE and FM/MDE groups with the MOE group having the highest pre-CRH stimulation mean cortisol levels (3.24 ng/dl) and post-CRH stimulation highest peak cortisol levels (9.88 ng/dl). Post-hoc analyses demonstrated significant differences in mean plasma cortisol levels between the FM/ADE and FM/MDE groups at the 1545 time point (p= .02), the 1600 time point (p= .004), and the peak plasma cortisol level (p= .001). No significant differences of IGF-1 levels were found among the three groups (p= .31 ). Conclusions: This study yielded four novel findings: 1) biological subtypes of major depressive disorder exist in FM and exhibit similar characteristics as those found in depressed non-FM populations, 2) atypical depressive episodes are more common than melancholic depressive episodes in this FM sample, 3) HPA axis suppression as evidenced by peak plasma cortisol levels are reflective of MOD subtypes, and 4) the use of the combined DEX/CRH stimulation test is feasible in an FM population and may demonstrate more sensitivity and specificity. Further research is needed to replicate the above results in a larger sample and to further evaluate the cost/benefit ratio of the more sensitive and specific combined DEX/CRH stimulation test versus the DST in FM patients with concurrent MOD.

Identifier

doi:10.6083/M48C9T9G

School

School of Nursing

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