However, several lines of evidence indicate that MLN8237 datasheet IFN-MDD may successfully inform us about MDD in general. First, a variety of studies have found

a robust relationship between IFN-α and MDE, including those demonstrating a dose-response relationship,19,20 studies with control groups,16,19-21 and prospective documentations of worsening depression during IFN-a treatment with a return to baseline mood after discontinuation.23-25 Thus, IFN-MDD is a replicable finding Inhibitors,research,lifescience,medical in prospective studies. Second, IFNMDD has phenomenological resemblance to MDD diagnosed in other situations.21-24 That is, IFN-MDD is not simply fatigue and malaise but – similarly to MDD – involves anhedonia, depressed mood, irritability, anxiety, social withdrawal, poor concentration, Inhibitors,research,lifescience,medical altered sleep, personality- changes, and suicidal ideation (Table I). Third, MDD and IFN-MDD may share similar pathophysiologic mechanisms, as indicated by various independent lines of investigation: Many inflammatory cytokines are elevated during MDD.51-53 Psychosocial stress can increase the levels of inflammatory cytokines.54,55

IFN-α and other cytokines can affect central monoaminergic systems plausibly involved in MDD.56-63 Peripheral cytokines and IFN-α have access to the CNS through a variety Inhibitors,research,lifescience,medical of routes in addition to being synthesized in the brain.64-66 Endogenous IFN-α mRNA can be induced in the cortex, hippocampus, and hypothalamus, with correlated changes in behavior in animal models of depression.64-67

Systemic administration of IFN-α and other cytokines can affect amotivation and anhedonia Inhibitors,research,lifescience,medical behaviors in rodent models of depression.68-75 Once IFN-MDD is diagnosed, it responds to treatments that are effective for idiopathic MDD, ranging from selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants to electroconvulsive therapy,15,76-85 with about 79% to 85% of patients responding to antidepressants.86,87 IFN-α administration can influence frontal lobe and anterior cingulate function,88,89 dopaminergic activity,60 and Inhibitors,research,lifescience,medical serotonergic function,90-93 – all of which may contribute to the development of depression in a manner ALOX15 homologous to other types of MDD. Table I. Comparison of Major Depressive Disorder (MDD) and interferon-a depressive disorder (IFN-MDD) during interferon-a treatment. Of further public health significance, the use of IFN-a is not rare. Almost 2% of the U.S. currently has chronic hepatitis C (HCV).94 IFN-a is the only FDA-approved treatment for HCV,95,96 whereas about 170 million people worldwide have been infected with HCV.97 Supporting IFN-α’s widespread use, untreated chronic HCV can lead to cirrhosis, hepatocellular cancer, and liver failure, resulting in about 10 000 deaths per year in the US,98 a rate which exceeds that from acquired immunodeficiency syndrome.99 Unfortunately, IFN-MDD can potentially result in suicide,38 dose reduction with risk for viral relapse,16 discontinuation of treatment,100,101 and lower quality of life.