A multidimensional analysis of the longitudinal effects of roux en y gastric bypass on fatigue: An association with visceral obesity.

BACKGROUND AND OBJECTIVES: Severe obesity is associated with fatigue, however, the effects of weight loss after bariatric surgery on particular dimensions of fatigue are unknown. In a secondary analysis of a prospective cohort study of women undergoing roux-en-y gastric bypass (RYGB) we explored relationships among multiple dimensions of fatigue and improving adiposity, insulin resistance and inflammation. METHODS: Before, and 1 and 6 months after RYBG, dimensions of fatigue were assessed using the validated, self-report, Multidimensional Fatigue Inventory. Total, abdominal visceral (VAT) and subcutaneous (SAT) adiposity, insulin sensitivity (Si and HOMA) and plasma concentrations of leptin, C-reactive protein (CRP) and interleukin-6 (Il-6) were measured using air displacement plethysmography, computed tomography, glucose tolerance testing and enzyme-linked immunoassay. Associations were assessed using Spearman correlations and linear regression. RESULTS: At baseline, the majority of our female participants (N = 19, body mass index, 46.5 kg/m2, age 37.2 years) were experiencing elevated levels of fatigue. By 6 months, dimensions of physical (-43%), reduced activity (-43%), reduced motivation (-38%), general (-31%; all p < .005), and mental (-18%, p < .05) fatigue improved, concomitant with decreases in markers of adiposity, inflammation and insulin resistance. The decrease in VAT was associated with improvement in mental fatigue (beta, 0.447 ±â€¯0.203, p = .045), independent of other indices of adiposity, IL-6 concentrations, or Si. CONCLUSIONS: In the 6 months after RYGB, fatigue improved, especially physical fatigue. Decreases in mental fatigue were strongly associated with decreases in visceral adiposity. Nevertheless, the biologic mechanisms underlying changes in these specific fatigue dimensions remain undetermined.

The effects of roux en y gastric bypass surgery on neurobehavioral symptom domains associated with severe obesity.

BACKGROUND: Neurobehavioral symptoms and cognitive dysfunction related to mood disorders are present in individuals with severe obesity. We sought to determine acute improvements in these symptoms and relationships with adiposity, inflammation, and insulin sensitivity after roux-en-y gastric bypass (RYGB) surgery. METHODS: The self-report Zung Depression Rating (ZDRS) and Neurotoxicity Rating (NRS) scales were administered before, and at 6-months after RYGB surgery in severely obese women (body mass index > 35 kg/m2; N = 19). Symptom domains corresponding to depressed mood/suicide ideation, anxiety, cognitive, somatic, and neurovegetative symptoms were assessed. Biologic measures were of adiposity [leptin, abdominal visceral (VAT) and subcutaneous (SAT) adipose tissue], inflammation [IL-6, C-reactive protein (CRP)], and insulin sensitivity (Si). Spearman correlations and linear regression (adjusted for biologic measures) assessed relationships between changes in biologic measures and changes in neurobehavioral domains. RESULTS: By 6-months after RYGB, VAT, SAT, Si, CRP, and IL-6 had improved (p < .05). Anxiety, somatic, and neurovegetative symptoms domains improved (p < .05), but depressed mood/suicidal ideation and cognitive domains did not. Reductions in VAT were associated with decreases in neurovegetative symptoms (beta = 295 ±â€¯85, p < .01). We also found significant positive longitudinal associations between IL-6 concentrations and minor changes in cognitive symptoms. CONCLUSION: Anxiety, somatic and neurovegetative symptoms, improved within 6 months after RYGB, but depressed mood/suicidal ideation and cognitive symptoms did not improve. Associations between visceral adiposity, IL-6 concentrations and neurovegetative and cognitive symptoms support links between obesity, inflammation and distinct neurobehavioral symptoms.

Risk factors for alcohol relapse following orthotopic liver transplantation: a systematic review.

BACKGROUND: Each year, 5000-6000 individuals undergo orthotopic liver transplantation (OLT) in the United States, and of these, nearly 18% have alcoholic liver disease. Relapse to alcohol occurs in more than 40% of patients with OLT for alcoholic liver disease. OBJECTIVES: We sought to identify factors that predict relapse to alcohol or medication nonadherence following OLT in patients with alcoholic liver disease and to review what randomized clinical interventions have addressed these factors following OLT. Our hypothesis was that there would be factors before and after OLT that predict relapse to alcohol following OLT, and that these, if targeted, might improve sobriety and associated outcomes of adherence with medications and appointments. METHODS: We performed a review (focusing on articles published since 2004) with PubMed and MEDLINE searches using the following search terms: liver transplantation, recidivism, alcohol relapse, and predictors of alcohol relapse. We supplemented the online searches with manual reviews of article reference lists and selected relevant articles for further review by author consensus. RESULTS: In largely white populations, prospective studies document that shorter length of pretransplantation sobriety is a significant predictor of time to first drink and time to binge use. Presence of psychiatric comorbidity, high score on standardized High-risk Alcoholism Relapse Scale, and diagnosis of Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) alcohol dependence are predictive of posttransplantation alcohol relapse. Pretransplantation alcohol use history variables (e.g., family history of alcoholism) reliably discriminate between complete abstainers and those who drink, while medical and psychosocial characteristics at early post-liver transplantation period (e.g., more bodily pain) maximally discriminate patterns of alcohol use. Alcoholic individuals with early-onset, rapidly accelerating moderate use and early-onset, continuously increasing heavy use have more than double the prevalence of steatohepatitis or rejection on biopsy and graft failure and more frequent mortality resulting from recurrent alcoholic liver disease than late-onset (i.e., peak of heaviest drinking at 6y posttransplantation) alcohol users do. Fortunately, pretransplantation screening combined with a structured pretransplantation management program and a 12-step program attendance reduced recidivism. No randomized clinical trials have been performed that target pretransplantation risk factors in individuals with alcoholic liver disease before or after OLT to improve post-OLT outcomes. CONCLUSIONS: Recent research findings suggest that screening can reveal individuals who are vulnerable to alcohol relapse and targeted intervention can prevent their relapse to alcohol. Based on existing addiction treatments (e.g., relapse prevention plan construction), randomized clinical trials tailored to post-OLT patients should be conducted to improve their survival and quality of life.

The biology of depression in cancer and the relationship between depression and cancer progression.

The prevalence of depressive symptoms in patients with cancer exceeds that observed in the general population and depression is associated with a poorer prognosis in cancer patients. The increased prevalence is not solely explained by the psychosocial stress associated with the diagnosis. Pro-inflammatory cytokines, which induce sickness behaviour with symptoms overlapping those of clinical depression, are validated biomarkers of increased inflammation in patients with cancer. A growing literature reveals that chronic inflammatory processes associated with stress may also underlie depression symptoms in general, and in patients with cancer in particular. Therapeutic modalities, which are frequently poorly tolerated, are used in the treatment of cancer. These interventions are associated with inflammatory reactions, which may help to explain their toxicity. There is evidence that antidepressants can effectively treat symptoms of depression in cancer patients though the database is meager. Novel agents with anti-inflammatory properties may be effective alternatives for patients with treatment-resistant depression who exhibit evidence of increased inflammation.

The impact of escitalopram on IL-2-induced neuroendocrine, immune, and behavioral changes in patients with malignant melanoma: preliminary findings.

Interleukin (IL)-2, a T-cell cytokine used to treat malignant melanoma, can induce profound depression. To determine whether pretreatment with the antidepressant escitalopram could reduce IL-2-induced neuroendocrine, immune, and neurobehavioral changes, 20 patients with Stage IV melanoma were randomized to either placebo or the serotonin reuptake inhibitor, escitalopram (ESC) 10-20 mg/day, 2 weeks before, and during IL-2 treatment (720 000 units/kg Q8 h × 5 days (1 cycle) every 3 weeks × 4 cycles). Generalized estimation equations were used to examine HPA axis activity (plasma ACTH and cortisol), immune activation (plasma IL-6), and depressive symptoms (Hamilton Depression Rating Scale (HDRS) score). Tolerance of IL-2 treatment (concomitant medications required) and adherence (number of IL-2 doses received) were also assessed. Both the groups (ESC (n=9), placebo (n=11)) exhibited significant IL-2-induced increases in plasma cortisol, IL-6, and depressive symptoms (p<0.05), as well as a temporal trend for increases in plasma ACTH (p=0.054); the effects of age and treatment were not significant. Higher plasma ACTH concentrations were associated with higher depressive symptoms during cycles 1-3 of IL-2 therapy (p<0.01). Although ESC had no significant effects on ACTH, cortisol, IL-6, tolerance of, or adherence to IL-2, ESC treatment was associated with lower depressive symptoms, ie, a maximal difference of ∼3 points on the HDRS, which, though not statistically significant (in part, due to small sample size), represents a clinically significant difference according to the National Institute for Health and Clinical Excellence guidelines. A larger sample size will establish whether antidepressant pretreatment can prevent IL-2-induced neurobehavioral changes.

Neurobehavioral effects of interferon-α in patients with hepatitis-C: symptom dimensions and responsiveness to paroxetine.

In patients at high risk for recurrence of malignant melanoma, interferon-α (IFN-α), a stimulator of innate immunity, appears to induce distinct neurobehavioral symptom dimensions: a mood and anxiety syndrome, and a neurovegetative syndrome, of which the former is responsive to prophylactic administration of paroxetine. We sought to determine whether symptom dimensions (and treatment responsiveness) arise in patients with hepatitis C administered IFN-α and ribavirin. In a randomized, double-blind, 6-month study, 61 patients with hepatitis C eligible for therapy with IFN-α and ribavirin received the antidepressant paroxetine (n=28) or a placebo (n=33). Study medication began 2 weeks before IFN-α/ribavirin therapy. Neuropsychiatric assessments included the 10-item Montgomery-Asberg Depression Rating Scale (MADRS). The items of the MADRS were grouped into depression, anxiety, cognitive dysfunction, and neurovegetative symptom dimensions, and analyzed using a mixed model. By 2 weeks of IFN-α/ribavirin therapy, all four dimensions increased, with the symptom dimensions of anxiety and cognitive dysfunction fluctuating and worsening, respectively, in both groups over time. The depression symptom dimension was significantly lower in the paroxetine treatment group (p=0.04); severity of the neurovegetative symptom dimension was similar in both groups. Similar to patients with malignant melanoma receiving high-dose IFN-α, the depression symptom dimension is more responsive to paroxetine treatment in individuals undergoing concomitant IFN-α/ribavirin therapy. However, the anxiety, cognitive dysfunction, and neurovegetative symptom dimensions appear less responsive to prophylactic paroxetine administration. Different neurobiologic pathways may contribute to the responsiveness of IFN-α-induced symptom dimensions to antidepressant treatment, requiring relevant psychopharmacologic strategies.

On-site Basic Health Screening and Brief Health Counseling of Chronic Medical Conditions for Veterans in Methadone Maintenance Treatment.

BACKGROUND: In order to improve the delivery of health services for chronic medical conditions in our methadone clinic, we added an onsite health screening and brief health counseling to the treatment plans for patients receiving methadone maintenance treatment at the Atlanta Veterans Affairs Medical Center (VAMC). We then conducted a follow up retrospective chart review to assess whether this intervention improved health outcome for those patients. METHODS: We reviewed the charts of one hundred and two patients who received treatment at Atlanta VAMC methadone clinic between 2002 and 2008. We sought to determine whether our increased health education and screening intervention was associated with improved: 1) Improved drug addiction outcome (as measured by comparing percentage of opiate and cocaine positive drug screens from admission to most recent). 2) Basic health screening, (as measured by the patient's compliance with primary care physicians (PCP) appointments and current smoking status). 3) Management of co-occurring medical conditions (as measured by levels of LDL cholesterol, hemoglobin A1c, and systolic blood pressure (SBP). 4) Presence of QTc prolongation (difference in QTc between baseline and most recent EKG). RESULTS: Illicit drug use (opiate and cocaine) markedly decreased in patients overall. The effect was more robust for those successfully "retained" (n=55, p<0.0001) in treatment, compared to those who "dropped out" (n=40, p=0.05) of treatment. Compliance with PCP appointments was high (82% and 88% before and after the onsite intervention, respectively) for "retained" patients. LDL cholesterol level was within normal range for all patients. A1c improved by 40% after the onsite intervention as reflected by the decreased percentage of patients with A1c > 7 % from before to after the intervention (90% vs. 50%, p=0.05). However, the prevalence of uncontrolled hypertension did not significantly improve after the onsite intervention (38% vs. 28%, p=0.34). As might be expected with MMT, the prevalence of QTc prolongation actually increased from 399 m sec. (+/- 92) to 439 msec. (+/- 22) after the onsite intervention (p=0.003). CONCLUSIONS: Our retrospective study supports the previous literature that methadone maintenance therapy is effective in reducing illicit drug use. Although patients with history of heroin dependence and in methadone maintenance treatment are at increased risk for chronic medical conditions like hepatitis C and diabetes, there are minimal federal guidelines for medical care, except than a physical exam upon admission, and basic screening for some infectious diseases e.g. HIV and Hepatitis C for those patients. Our study demonstrated the need for and potential benefit of enhancing the delivery of health promotion services for chronic medical conditions in methadone maintained patients. Improving management of hepatitis C, diabetes, hypertension, and other related conditions, in this high risk, difficult-to-treat, and underserved population may reduce their morbidity and premature mortality.

Depression and platelet activation in outpatients with stable coronary heart disease: findings from the Heart and Soul Study.

Depression is associated with increased morbidity and mortality in patients with coronary heart disease (CHD). Increased platelet activation has been proposed as a potential mechanism by which depression may lead to adverse cardiovascular outcomes. In this cross-sectional study, we measured platelet activation in 104 patients with stable CHD, including 58 with a current episode of major depression and 46 without past or current major depression. Participants were instructed not to take aspirin for 7 days prior to the study appointment. Platelet activation was measured by plasma concentrations of platelet factor 4 (PF4) and beta-thromboglobulin (beta-TG), and by 24-h urinary concentrations of 11-dehydro-thromboxane B(2) (TBXB2). We observed no differences in the mean levels of PF4, B-TG or TBXB2 in patients with and without major depression. Results were unchanged after adjustment for age, smoking, use of aspirin, and use of any psychotropic medication. We found no evidence of an association between major depression and platelet activation as measured by plasma concentrations of PF4 and beta-TG, or urinary TBXB2 in 104 outpatients with stable CHD. These findings do not support a role for platelet activation in the association between depression and cardiovascular disease among patients with stable CHD.

Sequential multiple-assignment randomized trial design of neurobehavioral treatment for patients with metastatic malignant melanoma undergoing high-dose interferon-alpha therapy.

BACKGROUND: Interferon-alpha therapy, which is used to treat metastatic malignant melanoma, can cause patients to develop two distinct neurobehavioral symptom complexes: a mood syndrome and a neurovegetative syndrome. Interferon-alpha effects on serotonin metabolism appear to contribute to the mood and anxiety syndrome, while the neurovegetative syndrome appears to be related to interferon-alpha effects on dopamine. PURPOSE: Our goal is to propose a design for utilizing a sequential, multiple assignment, randomized trial design for patients with malignant melanoma to test the relative efficacy of drugs that target serotonin versus dopamine metabolism during 4 weeks of intravenous, then 8 weeks of subcutaneous, interferon-alpha therapy. METHODS: Patients will be offered participation in a double-blinded, randomized, controlled, 14-week trial involving two treatment phases. During the first month of intravenous interferon-alpha therapy, we will test the hypotheses that escitalopram will be more effective in reducing depressed mood, anxiety, and irritability, whereas methylphenidate will be more effective in diminishing interferon-alpha-induced neurovegetative symptoms, such as fatigue and psychomotor slowing. During the next 8 weeks of subcutaneous interferon therapy, participants whose symptoms do not improve significantly will be randomized to the alternate agent alone versus escitalopram and methylphenidate together. RESULTS: We present a prototype for a single-center, sequential, multiple assignment, randomized trial, which seeks to determine the efficacy of sequenced and targeted treatment for the two distinct symptom complexes suffered by patients treated with interferon-alpha. LIMITATIONS: Because we cannot completely control for external factors, a relevant question is whether or not 'short-term' neuropsychiatric interventions can increase the number of interferon-alpha doses tolerated and improve long-term survival. CONCLUSIONS: This sequential, multiple assignment, randomized trial proposes a framework for developing optimal treatment strategies; however, additional studies are needed to determine the best strategy for treating or preventing neurobehavioral symptoms induced by the immunotherapy interferon-alpha.

The diagnosis of major depression in patients with cancer: a comparative approach.

Depressive symptoms not only impair quality of life in cancer patients but constitute an independent risk factor for increased mortality. In order to accurately and efficiently identify depression in cancer patients, the authors developed a biostatistical strategy to identify items of the 21-item, observer-rated Hamilton Rating Scale for Depression (Ham-D) that would optimize the diagnosis of depression among cancer patients. Exhibiting a relatively high sensitivity and specificity, our most optimal diagnostic tool contained six Ham-D items (late insomnia, agitation, psychic anxiety, diurnal mood variation, depressed mood, and genital symptoms). This study may serve as a prototype to generate valid instruments accurate for the diagnosis of major depression in other populations of cancer patients.

Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress.

OBJECTIVE: The authors sought to determine innate immune system activation following psychosocial stress in patients with major depression and increased early life stress. METHOD: Plasma interleukin (IL)-6, lymphocyte subsets, and DNA binding of nuclear factor (NF)-kB in peripheral blood mononuclear cells were compared in medically healthy male subjects with current major depression and increased early life stress (N=14) versus nondepressed male comparison subjects (N=14) before and after completion of the Trier Social Stress Test. RESULTS: Trier Social Stress Test-induced increases in IL-6 and NF-kappaB DNA-binding were greater in major depression patients with increased early life stress and independently correlated with depression severity, but not early life stress. Natural killer (NK) cell percentages also increased following stress. However, there were no differences between groups and no correlation between NK cell percentage and stress-induced NF-kappaB DNA-binding or IL-6. CONCLUSIONS: Male major depression patients with increased early life stress exhibit enhanced inflammatory responsiveness to psychosocial stress, providing preliminary indication of a link between major depression, early life stress and adverse health outcomes in diseases associated with inflammation.

A double-blind, multicenter, parallel-group study of paroxetine, desipramine, or placebo in breast cancer patients (stages I, II, III, and IV) with major depression.

OBJECTIVE: This study compared the efficacy and safety of paroxetine and desipramine with those of placebo in the treatment of depressive disorders in adult women with breast cancer, stages I-IV. METHOD: In a double-blind, placebo-controlled study, 35 female outpatients with breast cancer and DSM-III-R major depression or adjustment disorder with depressed mood were randomly assigned to treatment with paroxetine (N=13), desipramine (N=11), or placebo (N=11) for 6 weeks. Primary efficacy was assessed by change from baseline in score on the 21-item Hamilton Rating Scale for Depression (HAM-D), and the secondary outcome measure was change from baseline in the Clinical Global Impressions-Severity of Illness scale (CGI-S) score. RESULTS: Mean changes in the total HAM-D and CGI-S scores from baseline to 6-week endpoint for the paroxetine and desipramine groups were not significantly different than those for the placebo-treated group. An unusually high rate of response (defined as >or=50% improvement in the HAM-D score) in the placebo group was observed (55% [N=6]); adverse events precipitated patient discontinuation in the active treatment groups (9% [N=1] for desipramine, 15% [N=2] for paroxetine) similar to that in the placebo-treated patients (18% [N=2]). Improvement on symptom dimensions within the HAM-D and Hamilton Rating Scale for Anxiety (depressive, anxiety, cognitive, neurovegetative, or somatic) was also similar between groups. CONCLUSION: The small number of women in this study most likely contributed to the lack of observed differences in efficacy observed during the 6 weeks of treatment. Randomized, placebo-controlled trials of adequate power seeking to determine efficacy of antidepressants in the United States for the treatment of women with breast cancer and comorbid depression remain of paramount importance.

Mood disorders in the medically ill: scientific review and recommendations.

OBJECTIVE: The purpose of this review is to assess the relationship between mood disorders and development, course, and associated morbidity and mortality of selected medical illnesses, review evidence for treatment, and determine needs in clinical practice and research. DATA SOURCES: Data were culled from the 2002 Depression and Bipolar Support Alliance Conference proceedings and a literature review addressing prevalence, risk factors, diagnosis, and treatment. This review also considered the experience of primary and specialty care providers, policy analysts, and patient advocates. The review and recommendations reflect the expert opinion of the authors. STUDY SELECTION/DATA EXTRACTION: Reviews of epidemiology and mechanistic studies were included, as were open-label and randomized, controlled trials on treatment of depression in patients with medical comorbidities. Data on study design, population, and results were extracted for review of evidence that includes tables of prevalence and pharmacological treatment. The effect of depression and bipolar disorder on selected medical comorbidities was assessed, and recommendations for practice, research, and policy were developed. CONCLUSIONS: A growing body of evidence suggests that biological mechanisms underlie a bidirectional link between mood disorders and many medical illnesses. In addition, there is evidence to suggest that mood disorders affect the course of medical illnesses. Further prospective studies are warranted.

Breast cancer and depression.

Major depression and depressive symptoms, although commonly encountered in patients with medical illnesses, are frequently underdiagnosed and undertreated in women with breast cancer. Depression and its associated symptoms diminish quality of life, adversely affect compliance with medical therapies, and reduce survival. Treatment of depression in women with breast cancer improves their dysphoria and other depressive symptoms, enhances quality of life, and may increase longevity. In this review, studies that investigate pathophysiologic alterations in patients with cancer and comorbid depression are discussed, and the few studies on treatment of depression and related symptoms in women with breast cancer are examined.

Plasma homocysteine and immune activation in patients with malignant melanoma undergoing treatment with IFN-alpha.

Immune activation and cell proliferation may contribute to the development of increased homocysteine concentrations in patients with malignant diseases. In this study, we investigated the effect of interferon-alpha (IFN-alpha) on plasma homocysteine concentrations in patients being treated for malignant melanoma. In parallel, neopterin formation and tryptophan degradation were monitored to assess the capacity of IFN-alpha to activate macrophages. Plasma concentrations of homocysteine, folate, and vitamin B(12) were determined in 15 patients with malignant melanoma during 12 weeks of high-dose IFN-alpha therapy. Concurrently, concentrations of neopterin, tryptophan, and kynurenine were measured, and the kynurenine/tryptophan ratio (kyn/trp) was calculated. Homocysteine and folate concentrations during treatment with IFN-alpha did not differ from baseline. In contrast, significant increases in neopterin formation and tryptophan degradation were apparent during IFN-alpha therapy. Plasma concentrations of vitamin B(12) and cysteine also increased. These results indicate that IFN-alpha directly activates macrophages to release neopterin and to degrade tryptophan, but obviously treatment with INF-alpha did not affect homocysteine metabolism.

Interferon-alpha-induced changes in tryptophan metabolism. relationship to depression and paroxetine treatment.

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)-alpha 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-alpha treatment and continuing for the first 12 weeks of IFN-alpha therapy. At treatment initiation and at 2, 4, and 12 weeks of IFN-alpha 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-alpha 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-alpha-induced depressive symptoms, and paroxetine, although not altering the KYN or neopterin response to IFN-alpha, attenuates the behavioral consequences of IFN-alpha-mediated TRP depletion.

Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy.

OBJECTIVE: The authors assessed the relationship between the hypothalamic-pituitary-adrenal (HPA) axis response to interferon-alpha (IFN-alpha) and the development of major depression during IFN-alpha 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 IFN-alpha therapy, both immediately before and 1, 2, and 3 hours after IFN-alpha 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 IFN-alpha 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 IFN-alpha administration. CONCLUSIONS: The HPA axis response to the acute administration of IFN-alpha reveals a vulnerability to IFN-alpha-induced depression, possibly due to sensitization of corticotropin-releasing factor pathways.

Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions.

We have previously shown that the risk of major depression in patients with malignant melanoma undergoing interferon-alpha (IFN-alpha) therapy can be reduced by pretreatment with the antidepressant, paroxetine. Using dimensional analyses, the present study assessed the expression and treatment responsiveness of specific clusters of neuropsychiatric symptoms over the first three months of IFN-alpha therapy. Forty patients with malignant melanoma eligible for IFN-alpha treatment were randomly assigned to receive either paroxetine or placebo in a double-blind design. Neuropsychiatric assessments were conducted at regular intervals during the first twelve weeks of IFN-alpha therapy and included the 21-item Hamilton Depression Rating Scale, the 14-item Hamilton Anxiety Rating Scale and the Neurotoxicity Rating Scale. Neurovegetative and somatic symptoms including anorexia, fatigue and pain appeared within two weeks of IFN-alpha therapy in a large proportion of patients. In contrast, symptoms of depressed mood, anxiety and cognitive dysfunction appeared later during IFN-alpha treatment and more specifically in patients who met DSM-IV criteria for major depression. Symptoms of depression, anxiety, cognitive dysfunction and pain were more responsive, whereas symptoms of fatigue and anorexia were less responsive, to paroxetine treatment. These data demonstrate distinct phenomenology and treatment responsiveness of symptom dimensions induced by IFN-alpha, and suggest that different mechanisms mediate the various behavioral manifestations of cytokine-induced "sickness behavior."