Neurobehavioral Effects of Interferon-α in Patients with Hepatitis-C: Symptom Dimensions and Responsiveness to Paroxetine

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.

Psychomotor retardation and vulnerability to interferon alpha induced major depressive disorder: Prospective study of a chronic hepatitis C cohort

“…This is consistent with a higher baseline depression severity scale score (in the absence of clinical threshold MDD) appearing more likely in those who develop MDD during treatment [4,18]. Interest has developed into sub dimensions of IFNα induced depression (such as specific mood change, anxiety, cognitive dysfunction, somatic and neurovegetative/psychomotor symptom dimensions) which preliminary evidence has suggested all eventually increase during IFNα treatment, but neurovegetative/psychomotor and somatic features appear to increase earlier in treatment course [19,20]. Whether there is any greater pre-existing influence of each of these dimensions, particularly psychomotor and somatic features, on depression vulnerability during IFNα treatment has not been established.…”

“…They are clearly recognised as an adverse consequence of IFNα therapy and may represent a discrete syndrome, aside from specific mood change, which is more resistant to treatment and less responsive to serotonergic antidepressants than other symptoms [20,25]. A recent report also identified the baseline Beck Depression Inventory (BDI) item 'Fatigability' and Patient Health Questionnaire (PHQ-9) item 'Feeling tired or having little energy' as associated with later depressive disorder in a smaller interferon exposed cohort [26].…”

Inflammatory cytokines in depression: Neurobiological mechanisms and therapeutic implications

“…Interestingly, selective serotonin (5-HT) reuptake inhibitors (SSRIs) have been shown to alleviate cytokine-induced depression (Musselman et al, 2001a, Raison et al, 2007), and depressive and anxiety symptoms appear to be most responsive, while fatigue and neurovegetative symptoms are less responsive (Capuron et al, 2002, Raison et al, 2005b, McNutt et al, 2012). These data are consistent with findings in patients with advanced cancer undergoing chemotherapy who also exhibit increased inflammation in association with fatigue that is not responsive to SSRIs (Bower et al, 2002, Morrow et al, 2003, Miller et al, 2008).…”

“…In terms of the role of 5-HT in the treatment of cytokine-induced depression, SSRIs have been very effective in treating anxiety, depressed mood, and cognitive aspects of cytokine-induce depression, but not as effective for fatigue and neurovegetative symptoms (Capuron et al, 2002, Raison et al, 2005b, McNutt et al, 2012). As noted in section 2.5, these symptoms are often residual symptoms in medically healthy patients that are treated with SSRIs for major depression (Nierenberg et al, 2010, Targum and Fava, 2011).…”

Reduced kynurenine pathway metabolism and cytokine expression in the prefrontal cortex of depressed individuals

“…16 Supporting evidence linking the KP to depression stems from clinical studies showing that a number of patients receiving cytokine therapy experience changes in mood that correlate with re duced levels of TRP and increased levels of kynurenine and QUIN in the circulation. 17,18 Taken together with reports of in creased levels of cytokines and other markers of inflamma tion in the blood of depressed individuals, 19,20 these lines of evidence have led to the hypothesis that the pathophysiology of depression, in the absence of an overt inflammatory pro cess, may be related to a subsyndromal activation of the im mune system, resulting in chronic stimulation of the KP and altered glutamatergic activity. 3,8,9 Currently, the evidence implicating enhanced KP metab olism in depressed individuals in the absence of immunother apy or medical illness is both limited and inconsistent.…”