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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{at}virginia.edu (e-mail).

Key Words: Depression • Fibromyalgia • Menopause

Fibromyalgia is a musculoskeletal pain disorder characterized by chronic widespread pain, hypersensitivity to pain upon palpitation, and a range of functional disorders.¹ Estimates of lifetime prevalence are 3.4% for women and 0.5% for men.² Since fibromyalgia typically occurs in women at the onset of menopause, an estrogen deficit has been proposed as an associated factor.³ While the cause of fibromyalgia remains elusive, substantial findings implicate disturbances in the neuroendocrine axis as central to its etiology.⁴ Although no significant abnormalities in levels of estradiol, progesterone, or follicle stimulating hormone have been identified in premenopausal women with fibromyalgia,⁵ hyperactivity of the hypothalamic-pituitary-end organ axis has been suggested by higher cortisol levels with a flattened diurnal secretion pattern.⁶ 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.⁶

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.⁷ One of the most prevalent psychiatric disorders associated with fibromyalgia is depression, occurring in up to 80% of patients.⁷ 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.⁸ Furthermore, effects on levels of tryptophan (precursor of serotonin) and the tryptophan transport ratio⁹ may be mediated by estrogen, which may be dysregulated in peri- and 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.¹⁰ 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.¹¹

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.

Case Report

Ms. A was a 55-year-old, married, white woman referred by her primary care physician after several months of daily contact and frequent complaints. She reported lifelong anxiety and a prior history of major depression that had been treated for 10 years with desipramine, which was eventually discontinued because of anticholinergic side effects and emotional blunting. Following the discontinuation of desipramine, Ms. A was placed on a regimen of fluoxetine and continued taking this medication for the next 2 years. Ms. A eventually discontinued fluoxetine after complaining of increased appetite, decreased libido, and hot flashes. Attempts to initiate estrogen replacement therapy failed after she complained of intolerable side effects. At psychiatric evaluation, Ms. A reported 5 months of low energy, fatigue (especially with aerobic exercise), broken sleep, and early morning awakening (2 hours early). Other symptoms included difficulty concentrating, decreased memory, clouded thinking, angry/dysphoric mood, and anxiety with inappropriate worries focused on somatic symptoms. These complaints were further compounded with joint aches, blurred vision, coughing, lower extremity swelling, heavy limbs, weakness, and dizziness. Ms. A was unable to function in her career in real estate. Significant findings from her medical history included a recent diagnosis of fibromyalgia, viral hepatitis, chemical hepatitis (presumably from halothane), migraine headaches, irritable bowel syndrome, and menopause with intolerance to hormone replacement therapy. She reported allergies to five different medications (halothane, codeine, trimethoprim/sulfamethoxazole, indomethacin, and penicillin) and significant side effects with all medications.

Ms. A was diagnosed with moderate recurrent major depressive disorder complicated by fibromyalgia and menopause. All medications were started at low doses and titrated slowly because of the patient's prior sensitivity to medication side effects. Nefazodone was started at 50 mg b.i.d. and titrated over 6 weeks to 400 mg/day, which resulted in improved mood, decreased anxiety, and diminished somatic complaints. Sleep further improved with the full 400-mg dose at bedtime. Sustained-release bupropion was initiated for treatment of continued low energy, problems thinking, and decreased concentration and was slowly increased to 200 mg twice daily, which resulted in positive neurocognitive effects and enhanced energy. Aside from mild breast tenderness, initiation of a transdermal estrogen system was associated with full remission of the depression, and further improvements in somatic symptoms were reported at 0.075 mg/day. The only remaining symptoms were mild joint and muscle aches and fatigue with overexertion unaffected by nonsteroidal anti-inflammatory drugs. Regular exercise as part of a conditioning program was initiated. In light of the rare reports of liver failure temporally associated with the use of nefazodone, routine liver function test results were monitored because of Ms. A's past history of hepatitis; all test results remained within normal limits. The patient denied medication side effects, including sexual dysfunction. She returned to work and went months without contacting her primary care physician.

Discussion
There are a number of interesting points to this case. First, it demonstrates the effectiveness of combination therapy in a patient with depression complicated by fibromyalgia and menopause. Nefazodone is a very potent postsynaptic 5-HT₂ receptor antagonist that exhibits a moderate potency of inhibition for both serotonin and norepinephrine presynaptic transport proteins and has been shown to possess weak affinity for the ₁-adrenergic receptor.¹² The pharmacologic profiles of the novel antidepressants nefazodone^13–15 and venlafaxine^16,17 show promise in the management of pain, with better tolerability than the tricyclic antidepressants. Pick and colleagues¹⁴ conducted a preliminary study of mice in which nefazodone was associated with analgesia and an almost fourfold potentiation of analgesia when administered with an opioid (i.e., morphine). Similarly, the antinociceptive effect of venlafaxine appears to be associated with the kappa- and delta-opioid receptors combined with the ₂-adrenergic receptor. Further, there is evidence to show that the 5-HT₂ receptor may be involved in the mediation of pain;¹⁸ therefore antagonism of these receptors with a 5-HT₂ inhibitor may ameliorate pain.

In this patient with a complex disorder (fibromyalgia) and comorbid conditions (depression and menopause), combination treatment was necessary for a full therapeutic response and return of function. Nefazodone treated many of the depressive symptoms and the sleep disturbance associated with the fibromyalgia, improved tolerability to estrogen, and may have had analgesic effects. Sustained-release bupropion, with enhancing effects on dopamine and norepinephrine transmission, stabilized two additional neurotransmitter systems affecting mood and cognition and led to improved energy and neurocognitive effects. Bupropion has been demonstrated to improve attention, memory, and depression in children, adolescents, and adults with attention deficit hyperactivity disorder^19–21 and in elderly adults with depression.²² Estrogen may be helpful in perimenopausal women with major depression,²³ possibly related to improvement in associated climacteric symptoms,²⁴ but estrogen is poorly tolerated in women with fibromyalgia when the major depression is inadequately treated. Combined estrogen and antidepressant treatment is an effective treatment for peri- and postmenopausal women either when depression precedes the initiation of estrogen replacement therapy and does not respond to the therapy or when depression develops after estrogen replacement therapy has begun.²⁵ As such, the 5-HT effects modulated by nefazodone may have been further augmented by the estrogen presumably via several possible mechanisms (e.g., effects on 5-HT binding, metabolism, or degradation), while the cognitive improvements seen with bupropion may have been further enhanced by the effect of estrogen on the activity of the dopamine system.²⁶ The combined treatment with nefazodone, bupropion, and estrogen was very well tolerated in a woman with a previous history of multiple severe side effects with all medications, as is often seen in patients with fibromyalgia. This case suggests that targeted, combined treatment may be effective in women with comorbid fibromyalgia, depression, and menopause, but a larger case series is needed to test the efficacy of this combination.

ACKNOWLEDGMENTS

Supported in part by a grant from Bristol-Myers Squibb, Inc.

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