Early increase in vegetative symptoms predicts IFN-alpha-induced cognitive-depressive changes.
ABSTRACT The vegetative symptoms of depression resemble the symptoms of malaise associated with activation of the inflammatory response system (IRS), and can be regarded as an expression of a central motivational state that resets the organism's priorities to promote recovery from infection. Early vegetative symptoms, however, may also contribute to the high rates of depression seen later in the course of immune activation. We hypothesized that the onset of vegetative-depressive symptoms early in the treatment with the pro-inflammatory cytokine IFN-alpha in chronic hepatitis C patients would increase the risk for subsequent depressive cognitions.
Sixteen patients eligible for IFN-alpha treatment and free of psychiatric disorders were recruited. The DSM-IV, the Multidimensional Fatigue Inventory, and the Montgomery-Asberg Depression Rating Scale (MADRS) were administered at baseline and 1, 2, 4, 8, 12 and 24 weeks after treatment was initiated. Cognitive-depressive and vegetative-depressive symptom clusters were constructed.
Fatigue and depression scores increased significantly during IFN-alpha treatment. Depression scores were highest at week 8 of treatment. First week increase in vegetative-depressive symptom score predicted cognitive-depressive symptom score at week 8 and at week 24.
During IFN-alpha treatment, vegetative symptoms of depression appear earlier than, and are predictive of, their cognitive counterparts. This finding suggests that low mood state may in part be driven by the increase in early vegetative-depressive symptoms in the course of IFN-alpha-induced immune activation.
- SourceAvailable from: Charles L Raison
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- "Scores for each item range from 0 to 6 (total possible score ¼ 60), with higher scores indicating greater symptom severity. As discussed previously (Raison et al, 2007), the MADRS has been frequently used to measure depressive symptoms during IFN-a therapy, and shows improved internal consistency in patients with comorbid medical conditions compared with other clinician-administered questionnaires (Bonaccorso et al, 2002; Capuron et al, 2000; Constant et al, 2005; Hammond, 1998; Khan et al, 2004; Wichers et al, 2005). In addition to providing a continuous score of depressive symptoms, the following scores for the MADRS have been correlated with global severity measures of depression and have been used as 'cut-off' scores for levels of severity of depressive symptoms: mild, 15; moderate, 25; and severe, 31 (Kearns et al, 1982; Yonkers and Samson, 2000). "
ABSTRACT: 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.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 02/2012; 37(6):1444-54. DOI:10.1038/npp.2011.330 · 7.83 Impact Factor
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- "The effect of IFNα on cognitive function is still controversial. Though there appears to be little information available on the effect of IFNα on cognitive function in rats, a recent human study revealed no effect of IFNα on cognitive function after 6-month treatment in chronic hepatitis-C patients (Hilsabeck et al., 2005) whereas other investigator showed that the cognitive-depressive symptom score increased at eighth week of IFNα therapy (Wichers et al., 2005a). "
ABSTRACT: Treatment with pro-inflammatory cytokine, IFNalpha was documented to result in neuropsychiatric complications including depression and treatment with antidepressant, paroxetine could improve the depressive symptoms. Therefore, the effects of IFNalpha on behaviour and cytokine changes in the whole blood culture and in the prefrontal cortex, hypothalamus and hippocampus areas of the brain in wistar rats were investigated with emphasis on the role of paroxetine in the prevention of depressive behaviour induced by pro-inflammatory cytokines. The group of rats treated with IFNalpha (s.c. 50,000 IU/kg for 3 days/week for 5 weeks) was compared with three other groups; 1) saline control group (s.c. normal saline 0.2 ml/kg/day for 7 weeks), 2) paroxetine control group (paroxetine suspension orally 10 mg/kg/day for 7 weeks) and 3) group treated with paroxetine for 2 weeks followed by IFNalpha for 5 weeks. In open filed, the IFNalpha treated rats showed anxiety behaviour compared to the rats from the other groups. There was no significant difference in home cage emergence test, Morris water maze and object recognition test. There is no significant difference in plasma corticosterone between groups. The pro-inflammatory cytokines (TNFalpha, IL1beta and IFNgamma), were significantly higher whereas the anti-inflammatory cytokine, IL10 was lower in the stimulated whole blood culture of IFNalpha treated rats. In the brain, both pro-inflammatory cytokine IL1beta and anti-inflammatory cytokine IL10 were higher in hypothalamus of the IFNalpha treated rats; by contrast the concentration of IL10 was lowest in hippocampus region of this group compared to the other groups. The paroxetine pretreated rats did not show these cytokine changes following IFNalpha treatment. Thus it appears that paroxetine pretreatment prevents the pro-inflammatory changes in blood and brain following IFNalpha treatment in turn prevents the anxiety behaviour.Journal of Psychopharmacology 12/2007; 21(8):843-50. DOI:10.1177/0269881107077165 · 2.81 Impact Factor
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- "Associations over time were significant for the same three immune parameters (sIL-2r: B=8.16, Pb.001; TNF-a: B=10.3, P=.001; IL-6: B=5.28, Pb.001), with vegetative depressive symptoms as the dependent variable, and significant for two immune parameters (sIL-2r: B=2.11, Pb.001; IL-6: B=1.92, P=.001) for cognitive depressive symptoms. More details on the MADRS data in this sample are described elsewhere . "
ABSTRACT: Proinflammatory cytokines have the potential to activate the hypothalamo-pituitary-adrenocortical (HPA) axis, and HPA axis hyperactivity is also encountered in depression. Therefore, the induction of depressive symptoms by interferon-alpha (IFN-alpha) may be mediated by changes in the cytokine network and the HPA axis. In 17 hepatitis C patients undergoing IFN-alpha treatment, depressive symptoms were measured using the Montgomery-Asberg Depression Rating Scale (MADRS). In addition, serum cytokine concentrations were measured. Saliva was collected five times over the course of a day in order to assess daily average cortisol (DAC) and awakening response. Assessments were carried out at baseline and six later time points after starting treatment. During treatment, the increases in the MADRS were significantly and positively correlated with soluble interleukin (IL)-2 receptor, tumor necrosis factor alpha (TNF-alpha), and IL-6. There were no significant associations between the DAC or cortisol awakening response with the MADRS score. Results suggest a clear connection between IFN-alpha-induced depressive symptoms and cytokine concentrations, but not cortisol.Journal of Psychosomatic Research 03/2007; 62(2):207-14. DOI:10.1016/j.jpsychores.2006.09.007 · 2.84 Impact Factor