2009; Chen et al. 2010), HIV-related cognitive impairment (Toro-Nieves et al. 2009), dementia (Gomez Ravetti and Moscato 2008; EGFR phosphorylation Britschgi and Wyss-Coray 2009), multiple sclerosis (De Masi et al. 2009), pain disorders (Slade

et al. 2011; Alexander et al. 2012), and psychiatric disorders, including depression (Simon et al. 2008; Domenici et al. 2010; Arnold et al. 2012). Similarly, the results from this study strongly demonstrate the degree to which immune cell signaling proteins influence neuropsychiatric Inhibitors,research,lifescience,medical function in adults with and without HCV, and they suggest that efforts to develop and investigate novel immunotherapies as treatments for neuropsychiatric symptoms are warranted. As described Inhibitors,research,lifescience,medical above, our results show that BDNF, IL-23, RANTES, TNF-α, and TNFR2 may be of particular relevance to HCV-associated neuropsychiatric symptoms. Like many signaling proteins, these factors have dual roles as immunoregulators and neuromodulators, with the potential to both enhance inflammatory responses as well as adversely impact neuronal functions (e.g., target neurons Inhibitors,research,lifescience,medical for cell death, alter synaptic plasticity, hamper neuronal repair, enhance sensitivity to

pain or other stimuli) when upregulated. Thus, immunotherapies that are designed to simultaneously

“normalize” immunoregulation and Inhibitors,research,lifescience,medical neuromodulation may be particularly effective in treating neuropsychiatric symptoms, especially in individuals with chronic inflammatory conditions or infections such as HCV. Consistent with this approach, neurotransmitter-based antidepressants appear to have Inhibitors,research,lifescience,medical at least indirect anti-inflammatory effects and may partially reverse derangements in relevant inflammatory factors (Maes et al. 2009). Fluoxetine treatment for depression reduces serum IL-6 in patients (Sluzewska et al. 1995), and imipramine, clomipramine, venlafaxine, fluoxetine, sertraline, and trazodone have been shown to reduce unless the IFN-gamma/IL-10 ratio of human blood samples (a ratio of proinflammatory/anti-inflammatory drive), consistent with an anti-inflammatory effect (Sluzewska et al. 1995; Maes et al. 1999; Kubera et al. 2001). In addition, nonresponders to selective serotonin reuptake inhibitor medication continue to exhibit elevated IL-6 levels, raising the possibility that response to treatment is linked to a reduction in IL-6 (O’Brien et al. 2007). Thus, immunotherapies that more directly target immune cell signaling may prove efficacious as primary or adjunct treatments for neuropsychiatric disorders.