Combination therapy in the treatment of major depressive disorder complicated by fibromyalgia and menopause.

Received March 6, 2002; revision received April 17, 2002; accepted April 26, 2002. From the Department of Psychiatric Medicine, University of Virginia; and the Medical Neuroscience Division, Bristol-Myers Squibb Company, Plainsboro, N.J. Address reprint requests to Dr. Clayton, Department of Psychiatric Medicine, University of Virginia, 2955 Ivy Rd., Northridge Suite 210, Charlottesville, VA 22903; ahc8v@virginia.edu (e-mail). Copyright 2002 The Academy of Psychosomatic Medicine. Fibromyalgia is a musculoskeletal pain disorder characterized by chronic widespread pain, hypersensitivity to pain upon palpitation, and a range of functional disorders. Estimates of lifetime prevalence are 3.4% for women and 0.5% for men. Since fibromyalgia typically occurs in women at the onset of menopause, an estrogen deficit has been proposed as an associated factor. While the cause of fibromyalgia remains elusive, substantial findings implicate disturbances in the neuroendocrine axis as central to its etiology. Although no significant abnormalities in levels of estradiol, progesterone, or follicle stimulating hormone have been identified in premenopausal women with fibromyalgia, hyperactivity of the hypothalamic-pituitaryend organ axis has been suggested by higher cortisol levels with a flattened diurnal secretion pattern. Abnormalities in corticotropin-releasing hormone neurons may influence response to stress, alter the central mechanism of nociception, change the set point of other hormones mediated through the hypothalamic-pituitary-end organ axis, and induce hypofunction of neurotransmitter systems affecting mood, motivation, and somatic processes such as sleep. As with other chronic pain syndromes, fibromyalgia is associated with comorbid psychiatric symptoms including sleep disturbances, mood lability, fatigue, and somatization. In fact, extensive evidence suggests that the comorbid psychiatric distress of fibromyalgia patients is significantly higher than that of other chronic pain patients. One of the most prevalent psychiatric disorders associated with fibromyalgia is depression, occurring in up to 80% of patients. Altered serotonin (5-HT) metabolism associated with reduced transcription activity of the short allele of the serotonin transporter occurs more frequently in patients with fibromyalgia than in healthy comparison subjects and has been linked to higher levels of depression and psychological distress. Furthermore, effects on levels of tryptophan (precursor of serotonin) and the tryptophan transport ratio may be mediated by estrogen, which may be dysregulated in periand postmenopausal women. Antidepressants have been commonplace in the treatment of fibromyalgia because of their established efficacy in the treatment of depression and their abilities to modulate nociceptive responses. Tricyclic antidepressants have been the most widely studied antidepressant medication class for the treatment of fibromyalgia because of both their analgesic and antidepressant effects. Despite significant data from controlled trials indicating that tricyclic antidepressants are effective analgesics, the issues of safety and tolerability still exist when using these drugs at therapeutic doses for comorbid symptoms of depression. Newer antidepressant medications lacking these properties have therefore been of interest for disease states such as fibromyalgia. Furthermore, newer agents may also be more effective in women. Because of potential complex interactions between the hypothalamic-pituitary-end organ axis, sex steroids, and nociceptive responses, single therapies have been minimally effective. Combination therapy may be required for full remission of psychiatric symptoms associated with fibromyalgia. To date, there have been very little data to support the combination of nefazodone and bupropion in the treatment of major depression or fibromyalgia in postmenopausal women. We present a case of major depressive disorder complicated by fibromyalgia and menopause that responded to the combination of nefazodone and bupropion in conjunction with estrogen replacement therapy.