Raison CL, Borisov AS, Broadwell SD, Capuron L, Woolwine BJ, Jacobson IM, Nemeroff CB, Miller AH. Journal of Clinical Psychiatry 2005;66:41-48 Depression during pegylated IFN-alpha plus ribavirin therapy: prevalence and prediction. Summary This is a report from one of several 'modeling' studies conducted by the CDC CFS collaborative research group. Perturbations of the immune system likely play a role in the pathophysiology of CFS but studies to date have been complicated by patient heterogeneity with respect to chronicity and co-morbid illnesses. 'Model' systems, in which symptom-free subjects develop CFS-like illness following exposure to a known immune system stimulus, obviate these problems and permit controlled studies of the pathophysiology of fatigue and associated symptoms as they relate to immune and endocrine activation. Interferon-alpha (IFN-alpha), a cytokine used in the treatment of hepatitis C, activates the immune system and produces an illness resembling CFS (e.g. fatigue, cognitive complaints, pain, sleep disturbance, and depression) and we are using this to help understand the symptoms and pathophysiology of CFS. This particular publication documents that depression occurs along with other symptoms of CFS following immune activation. The occurrence of depression was primarily predicted by prior depression. Abstract Background: Interferon-alpha (IFN-alpha) plus ribavirin is used to treat hepatitis C virus (HCV) infection and is associated with a high rate of depression. Newer, pegylated preparations of IFN-alpha have a longer half-life, require once-per-week dosing, and may be associated with reduced neuropsychiatric burden. Limited data exist on depression during pegylated IFN-alpha therapy. Method: Depressive symptoms were assessed using the Zung Self-Rating Depression Scale (SDS) in 162 HCV-infected patients at baseline and after 4, 8, 12, and 24 weeks of treatment with pegylated IFN alpha-2b (PEG IFN) plus weight-based (N = 86) versus standard dose (N = 76) ribavirin. Data were collected from March 2001 to April 2003. RESULTS: Compared with baseline, mean SDS index scores were significantly increased by week 4 and remained elevated throughout the study. Thirty-nine percent of the sample experienced moderate to severe depressive symptoms (SDS index score > or = 60) at some point during PEG IFN/ribavirin therapy. Baseline depression scores significantly predicted severity of depressive symptoms during PEG IFN/ribavirin treatment (simple regression analysis: Y = 0.55X + 32.7, p < .0001). In addition, assignment to weight-based ribavirin treatment and history of depression were associated with increased likelihood of developing moderate to severe depressive symptoms (odds ratio [OR] = 2.7, 95% CI = 1.3 to 5.6, p < .01, and OR = 3.3, 95% CI = 1.3 to 8.1, p < .01, respectively). Conclusions: Development of moderate to severe depressive symptoms occurred frequently during PEG IFN/ribavirin treatment and was predicted by baseline depression scores and higher doses of ribavirin. History of major depressive disorder was also a significant predictive factor, but only through association with elevated baseline depression status. All of these factors can be evaluated and addressed to limit neuropsychiatric morbidity during HCV treatment. ---------------------------------------- [Further background info from CDC site] http://www.cdc.gov/ncidod/diseases/cfs/hot_topics/8.01_update.htm Chronic Fatigue Syndrome Program Program Update August 29, 2001 Modeling studies: alpha interferon-induced fatigue. Patients with chronic hepatitis C or malignant melanoma who have been treated with interferon-alpha (INF-a) frequently develop symptoms of CFS. Thus, a CDC/Emory University Collaborative Group has undertaken a series of studies using INF-a-associated fatigue to model CFS. The cornerstone of these studies is a project under way in the Emory University Clinical Research Center that measures immune and neuroendocrine parameters, sleep, metabolism, mood changes, and mRNA expression patterns in INF-a recipients who develop a CFS-like illness compared with those who do not. To date, 8 patients have been enrolled (target enrollment: 50 subjects). Findings from this study will be integrated with results of a similar analysis of these functions in CFS patients (see Wichita clinical studies discussed below). Other studies by this collaborative group include an integration of comprehensive fatigue measures in ongoing assessments of patients receiving IFN-a for malignant melanoma and hepatitis C. Early findings from these studies indicate that the development of fatigue is distinct from the development of mood disorders (depression) both in terms of symptom evolution and treatment responsiveness (fatigue appears early during interferon administration and does not respond to antidepressant treatment, whereas depressive symptoms develop later and are antidepressant responsive). These results are consistent with findings in subjects with post-infectious fatigue and are under review for publication. ---------------------------------------------------------------------------- http://www.cdc.gov/ncidod/diseases/cfs/program-updates/cfs-uptdate-031703.ht m CHRONIC FATIGUE SYNDROME PROGRAM Program Update 2002-2003 Emory Collaboration - Department of Psychiatry. Interferon-á (IFN-á), a cytokine widely used in the treatment of hepatitis C (HCV) and malignant melanoma, represents a model system of great promise, because IFN-á activates the immune system and produces a high rate of symptoms commonly observed in CFS (fatigue, cognitive complaints, pain, sleep disturbance and depression). Thus, a CDC/Emory University Collaborative Group has undertaken a series of integrated studies using IFN-á-associated fatigue to model CFS. Interferon-á-Induced Sickness Syndrome as a Model for the Pathophysiology of Chronic Idiopathic Fatigue. We measure immune and neuroendocrine parameters, sleep, metabolism, brain activity, mood changes, and mRNA expression patterns in IFN-á recipients with HCV infection. Subjects are studied prior to, and after 12 weeks, of receiving IFN-á. HCV subjects randomized to postpone treatment until study completion serve as HCV+ controls. All study subjects undergo sleep polysomnography, body composition analysis, resting metabolic rate assessment and physical activity assessment at home via actigraphy. Subjects receive hourly blood draws for assessment of plasma cortisol, ACTH, norepinephrine, epinephrine, and cytokines (interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)- á, and soluble receptors for TNF-á and IL-6). Subjects also receive a lumbar puncture following 12 weeks of treatment with IFN-á. The lumbar puncture assesses cerebrospinal fluid concentrations of corticotropin-releasing hormone (CRH), ACTH, cortisol, norepinephrine, epinephrine, and proinflammatory cytokines (i.e. IL-1, IL-6, TNF-á). Eleven patients have been enrolled with a target enrollment of 50 subjects. Findings from this study will be integrated with results of a similar analysis of these functions in CFS patients from the Wichita clinical study and with data from a study of post-infectious fatigue in Australia. We are measuring gene expression profiles in these three studies so the data can be compared and integrated to define relevant common pathways requisite to the expression of fatigue and CFS. ---------------------------------------------------------------------------- http://www.cdc.gov/ncidod/diseases/cfs/publications/causes.htm Capuron L, Raison CL, Musselman DL, Lawson DH, Nemeroff CB, Miller AH American Journal of Psychiatry 2003;160:1342-1345 Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy. Summary Emory University Department of Psychiatry and Behavioral Sciences faculty who are also members of the CDC/Emory University Collaborative CFS Research Program published this article under partial support of the CFS research program. Studies examining the pathophysiology of CFS have been complicated by patient heterogeneity with respect to chronicity and co-morbid illnesses. "Model" systems in which symptom-free subjects develop CFS-like illness following exposure to a known immune system stimulus obviate these problems and permit controlled studies of the pathophysiology of fatigue and associated symptoms as they relate to immune and endocrine activation. Interferon-alpha (IFN-alpha), a cytokine widely used in the treatment of hepatitis C and malignant melanoma, represents a model system of great promise, given that IFN-alpha activates the immune system and produces a high rate of symptoms commonly observed in CFS, including fatigue, cognitive complaints, pain, sleep disturbance and depression. Thus, the CDC/Emory University Collaborative Group has undertaken a series of integrated studies using INF-alpha-associated fatigue to model CFS. One important question concerns the relationship between depression and CFS. Patients who receive INF-alpha develop CFS-like illness that has overlapping features with major depression. This study sought to determine whether differences in neuroendocrine response to INF-alpha could predict development of major depression apart from other symptoms. They found that patients who developed depression following INF-alpha treatment had subclinical behavioral symptoms before challenge and hypothesize that patients who develop depression associated with CFS-like illness may have a more generalized hyperresponsiveness to stress. Abstract Objective: The authors assessed the relationship between the hypothalamic-pituitary-adrenal (HPA) axis response to interferon-alpha (INF-a) and the development of major depression during INF-a treatment. Method: Adrenocorticotropic hormone (ACTH), cortisol, and interleukin-6 (IL-6) plasma concentrations were measured in 14 patients with malignant melanoma at regular intervals during the first 12 weeks of INF-a therapy, both immediately before and 1, 2, and 3 hours after INF-a administration. Symptom criteria for major depression were also evaluated at each visit. Results: ACTH and cortisol responses but not IL-6 responses to the initial administration of INF-a were significantly higher in the seven patients who subsequently developed symptom criteria for major depression than in those who did not. No differences in hormonal or cytokine responses were found between these two groups during chronic INF-a administration. Conclusions: The HPA axis response to the acute administration of INF-a reveals a vulnerability to INF-a induced depression, possibly due to sensitization of corticotropin-releasing factor pathways. ---------------------------------------------------------------------------- Capuron L, Neurauter G, Musselman DL, Lawson DH, Nemeroff CB, Fuchs D, Miller AH Biological Psychiatry 2003;54:906-914 Interferon-Alpha-Induced Changes in Tryptophan Metabolism: Relationship to Depression and Paroxetine Treatment. Summary Emory University Department of Psychiatry and Behavioral Sciences faculty who are also members of the CDC/Emory University Collaborative CFS Research Program published this article under partial support of the CFS research program. Studies examining the pathophysiology of CFS have been complicated by patient heterogeneity with respect to chronicity and co-morbid illnesses. "Model" systems in which symptom-free subjects develop CFS-like illness following exposure to a known immune system stimulus obviate these problems and permit controlled studies of the pathophysiology of fatigue and associated symptoms as they relate to immune and endocrine activation. Interferon-alpha (IFN-alpha), a cytokine widely used in the treatment of hepatitis C and malignant melanoma, represents a model system of great promise, given that IFN-alpha activates the immune system and produces a high rate of symptoms commonly observed in CFS, including fatigue, cognitive complaints, pain, sleep disturbance and depression. Thus, the CDC/Emory University Collaborative Group has undertaken a series of integrated studies using INF-alpha-associated fatigue to model CFS. Previous studies by the group have shown that the antidepressant paroxetine was effective in preventing the development of major depression in patients receiving INF-alpha therapy for malignant melanoma but had a minimal effect on fatigue and pain. This suggests that the core symptoms of CFS (in the context of immune activation) have a different natural history and treatment response than do core symptoms of major depression. This study investigated physiologic parameters that might explain the differences. Similar to the findings with neuroendocrine responses, alterations in the metabolism of the neurotransmitter, serotonin, also appear to be involved in the development of mood/anxiety symptoms but not fatigue. Indeed, IFN-alpha-induced decreases in tryptophan (the primary precursor of serotonin) and increases in the tryptophan metabolite, kynurenine, reflecting activation of the enzyme, indolamine 2,3, dioxygenase, were associated with the development of depressive symptoms but not neurovegetative symptoms (e.g. fatigue and psychomotor slowing) in patients with malignant melanoma. These findings suggest that immune activation may produce fatigue via effects of cytokines on dopamine neurotransmission in the basal ganglia, while major depression develops as a function of IFN-alpha-induced effects on the neuroendocrine (CRH) system and monoamine (serotonin) metabolism. These potential neurobiological differences between immune-mediated fatigue and depression in patients receiving IFN-alpha are especially intriguing in light of data demonstrating that while major depression and CFS are frequently comorbid, the two conditions are also clearly separable and need not occur together. Abstract Background: Tryptophan (TRP) degradation into kynurenine (KYN) by the enzyme, indoleamine-2,3-dioxygenase, during immune activation may contribute to development of depressive symptoms during interferon (IFN)- a therapy. Methods: Twenty-six patients with malignant melanoma were randomly assigned in double-blind fashion to receive either placebo or paroxetine, beginning 2 weeks before IFN-a treatment and continuing for the first 12 weeks of IFN-a therapy. At treatment initiation and at 2, 4, and 12 weeks of IFN-a treatment, measurements of TRP, KYN, and neopterin (a marker of immune activation), were obtained, along with structured assessments of depression, anxiety, and neurotoxicity. Results: Regardless of antidepressant treatment status, all patients exhibited significant increases in KYN, neopterin, and the KYN/TRP ratio during IFN-a therapy. Among antidepressant-free patients, patients who developed major depression exhibited significantly greater increases in KYN and neopterin concentrations and more prolonged decreases in TRP concentrations than did nondepressed, antidepressant-free patients. Moreover, in antidepressant free patients, decreases in TRP correlated with depressive, anxious, and cognitive symptoms, but not neurovegetative or somatic symptoms. No correlations were found between clinical and biological variables in antidepressant-treated patients. Conclusions: The results suggest that reduced TRP availability plays a role in IFN-a -induced depressive symptoms, and paroxetine, although not altering the KYN or neopterin response to IFN-a , attenuates the behavioral consequences of IFN-a -mediated TRP depletion.