Because of its antiviral and immunomodulatory properties, the cytokine interferon-ct (INF-ct) has become a standard treatment for hepatitis C. While INF treatment is demonstratively efficacious, it produces a number of side effects including flu-like symptoms, e.g., fever, tachycardia, headache, and malaise, which tend to appear early in treatment and abate as treatment continues. In addition, INF produces neuropsychiatric symptoms including depression that emerge later in treatment and persist throughout. Animal studies repeatedly have shown that experimental administration of cytokines produces a syndrome called """"""""sickness behavior"""""""" that resembles human depression. This evidence suggests that patients scheduled to receive INF treatment constitute a high-risk model of depression that can be used to examine the neurobiology of the disorder. ? ? The mechanism of these neuropsychiatric side effects of cytokines in general and INF-c_in particular is unclear. Evidence suggests the involvement of central neurotransmitters: prophylactic treatment with antidepressant medications such as tricyclic anti-depressants and selective serotonin reuptake inhibitors (SSRIs) prevents the INF-(x-produced depression and INF-a is known to initiate a cascade of cytokine release linked to the serotonin system. Animal studies report that INF induces increased serotonin transporter levels and the consequence of this may be to lower intra-synaptic serotonin concentrations, creating a hypo-serotonergic state that precipitates depression in vulnerable individuals analogous to the depression produced by an acute tryptophan depletion. Such a novel mechanism is different from the pathobiological picture identified by postmortem and in vivo imaging studies in major depressive episodes. Such studies find reduced transporter binding which is not due to the effects of antidepressant treatment and may well be a homeostatic response to low intra-synaptic serotonin due to other causes. Accumulation of more definitive evidence on the pathobiology of INF-produced depression and the prophylactic effect of antidepressant treatment is important for two reasons: 1) the neuropsychiatric side effects of INF treatment are the primary reason for discontinuation of treatment (1)] and 2) such evidence may shed light on the pathophysiologic mechanisms of MDD. ? ? Therefore, the aims of this application for an exploratory award are two-fold: 1) to determine whether patients undergoing INF treatment who develop major depression will show an increase in binding to the serotonin transporter quantified by PET; and 2) to compare the pathobiology of a major depressive episode in medically healthy untreated individuals with a major depression produced by INF treatment in patients with hepatitis C. ? ?
| Shapiro, Peter A; Sloan, Richard P; Deochand, Chetram et al. (2014) Quantifying serotonin transporters by PET with [11C]-DASB before and after interferon-? treatment. Synapse 68:548-55 |
