Anterior cingulate activation and error processing during interferon-alpha treatment

Background: There has been increasing interest in the role of immunologic processes, notably cytokines, in the development of behavioral alterations, especially in medically ill patients. Interferon (IFN)-α is notorious for causing behavioral symptoms, including depression, fatigue, and cognitive dysfunction, and has been used to investigate the effects of cytokines on the brain. Methods: In the present study we assessed the effects of low-dose IFN-α on brain activity, using functional magnetic resonance imaging during a task of visuospatial attention in patients infected with hepatitis C virus (HCV). Results: Despite endorsing symptoms of impaired concentration and fatigue, IFN-α-treated patients (n = 10) exhibited task performance and activation of parietal and occipital brain regions similar to that seen in HCV-infected control subjects (n = 11). Interestingly, however, in contrast to control subjects, IFN-α-treated patients exhibited significant activation in the dorsal part of the anterior cingulate cortex (ACC), which highly correlated with the number of task-related errors. No such correlation was found in control subjects. Conclusions: Consistent with the role of the ACC in conflict monitoring, ACC activation during IFN-α administration suggests that cytokines might increase processing conflict or reduce the threshold for conflict detection, thereby signaling the need to exert greater mental effort to maintain performance. Such alterations in ACC activity might in turn contribute to cytokine-induced behavioral changes

Depression during pegylated interferon-alpha plus ribavirin therapy: Prevalence and prediction

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 ≥ 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 lo limit neuropsychiatric morbidity during HCV treatment

Arch Gen Psychiatry

Inflammatory cytokines or cytokine inducers can alter basal ganglia activity, including reducing responsiveness to rewarding stimuli that may be mediated by cytokine effects on dopamine function. To determine whether long-term administration of the inflammatory cytokine interferon alfa reduces the basal ganglia response to reward and whether such changes are associated with decreased presynaptic striatal dopamine function and altered behavior. Cross-sectional and longitudinal studies. Outpatient research unit and neuroimaging facilities at Emory University, Atlanta, Georgia. Medically stable adults with chronic hepatitis C virus (HCV) infection eligible for interferon alfa treatment. Neural activity in the ventral striatum during a hedonic reward task as measured by functional magnetic resonance imaging, uptake and turnover of radiolabeled fluorodopa F 18 (18F-dopa) in caudate and putamen using positron emission tomography, and interferon alfa-induced depression, anhedonia, fatigue, and neurotoxicity. Patients with HCV receiving interferon alfa for 4 to 6 weeks (n = 14) exhibited significantly reduced bilateral activation of the ventral striatum in the win vs lose condition of a gambling task compared with patients with HCV awaiting interferon alfa treatment (n = 14). Reduced activation of the ventral striatum was, in turn, significantly correlated with anhedonia, depression, and fatigue. In a separate longitudinal study, patients with HCV treated with interferon alfa for 4 to 6 weeks (n = 12) exhibited significantly increased 18F-dopa uptake and decreased 18F-dopa turnover in caudate and putamen and in the same ventral striatal regions identified in the functional magnetic resonance imaging study. Baseline and percentage change in 18F-dopa uptake and turnover were correlated with behavioral alterations, including depression, fatigue, and neurotoxicity, during interferon alfa administration. These data replicate and extend findings that inflammatory stimuli, including inflammatory cytokines, such as interferon alfa, alter basal ganglia activity and behavior in association with significant changes in presynaptic striatal dopamine function consistent with decreased dopamine synthesis or release

Depressive symptoms and viral clearance in patients receiving interferon-α and ribavirin for hepatitis C

Interferon (IFN)-α plus ribavirin is an effective treatment for hepatitis C virus (HCV) infection, but is associated with a high rate of depression. Depression has been linked to a worse outcome in multiple medical disorders including viral illnesses. We examined whether increased symptoms of depression during IFN-α/ribavirin therapy were associated with a reduced treatment response as assessed by clearance of HCV. Depressive symptoms were evaluated in 102 HCV-infected patients at baseline and after 4, 8, 12, and 24 weeks of pegylated IFN-α-2b plus ribavirin therapy using the Zung self-rating depression scale (SDS). Viral clearance was determined at 24 weeks by polymerase chain reaction (PCR). Only 34% of subjects (10 out of 29) with a 20-point or greater increase in SDS Index score were HCV PCR negative at 24 weeks, compared to 59% (24 out of 41) of patients with a 10–19 point increase in SDS Index and 69% (22 out of 32) of patients with a less than 10 point increase ( χ 2=7.6, df=2, p<0.05). In addition, a 20-point or greater increase in SDS Index score during IFN-α/ribavirin therapy significantly predicted failure to clear virus when considered alone [crude odds ratio (OR), 3.2; 95% confidence interval (CI), 1.3–8.0; p<0.01] or when controlling for other factors that affected IFN-α treatment response (adjusted OR, 3.6; 95% CI, 1.3–9.5; p=0.01). These preliminary findings suggest that individuals who experience significant increases in depressive symptoms during IFN-α/ribavirin therapy may be less likely to clear virus, highlighting the importance of identifying and treating depressive symptoms in this patient population

Inflammatory markers are associated with decreased psychomotor speed in patients with major depressive disorder

Previous data have demonstrated that administration of inflammatory cytokines or their inducers leads to altered basal ganglia function associated with reduced psychomotor speed. Decreased psychomotor speed, referred to clinically as psychomotor retardation, is a cardinal symptom of major depressive disorder (MDD) and has been associated with poor antidepressant treatment response. We therefore examined the association between plasma inflammatory markers and psychomotor speed in ninety-three un-medicated patients with MDD. Psychomotor speed was assessed by a range of neuropsychological tests from purely motor tasks (e.g. movement latency and finger tapping) to those that involved motor activity with increasing cognitive demand and cortical participation (e.g. Trails A and Digit Symbol Substitution Task (DSST)). Linear regression analyses were performed to determine the relationship of inflammatory markers and psychomotor task performance controlling for age, race, sex, education, body mass index, and severity of depression. MDD patients exhibited decreased psychomotor speed on all tasks relative to normative standards. Increased IL-6 was associated with decreased performance on simple and choice movement time tasks, whereas MCP-1 was associated with decreased performance on the finger tapping task and DSST. IL-10 was associated with increased performance on the DSST. In an exploratory principle component analysis including all psychomotor tasks, IL-6 was associated with the psychomotor speed factor. Taken together, the data indicate that a peripheral inflammatory profile including increased IL-6 and MCP-1 is consistently associated with psychomotor speed in MDD. These data are consistent with data demonstrating that inflammation can affect basal ganglia function, and indicate that psychomotor speed may be a viable outcome variable for anti-inflammatory therapies in depression and other neuropsychiatric disorders with increased inflammation