There is some evidence that antidepressant drugs have direct immunomodulatory effects, particularly when administered chronically.128 Many studies have reported that the depression induced by the therapeutic administration of cytokines is responsive to antidepressants,63,74 and remission of symptoms following antidepressant treatment may be associated with normalization of cytokine levels.66 Furthermore, alterations in cytokine levels are predictive of treatment response: increased levels of TNF-α are lowered Inhibitors,research,lifescience,medical by

antidepressant administration in patients who respond to the treatment, but not in nonresponders.67 In MS, successful antidepressant treatment of depressive symptoms is associated with normalized levels of IFN-γ5 Increased IFN-γ levels precede exacerbations and correlate with more aggressive Inhibitors,research,lifescience,medical Caspase activity disease course, suggesting that the immunomodulatory actions of antidepressants may be generally relevant in the treatment of MS, in addition to their efficacy for depressive symptoms.5 Further suggesting an intimate relationship between depression and inflammation, some antidepressants have been shown to have direct anti-inflammatory effects in autoimmune or infectious diseases.129 Bupropion in particular has been shown to have several interesting

potential immunomodulatory effects: (i) bupropion has been associated with the induction Inhibitors,research,lifescience,medical of remission in Crohn’s disease in patients even in absence of depression; (ii) Inhibitors,research,lifescience,medical bupropion led to the lowering of circulating TNF in a patient with hepatitis B infection; and (iii) bupropion profoundly lowers levels of TNF, IFN-γ, and IL-1β in vivo, in a mouse inflammation model of sepsis. Whether the immunomodulatory effects of some antidepressants play a supplementary role in their mechanism of treatment response for depression remains to be elucidated. Neurogenesis and treatment response The possibility that impaired neurogenesis contributes to depression Inhibitors,research,lifescience,medical suggests a novel mechanism for the action of antidepressants: a restoration of normal hippocampal

neurogenesis. Consistent with this possibility, mafosfamide antidepressants enhance hippocampal neurogenesis both in vitro and in vivo,130-133 and this effect requires chronic treatment, consistent with the time course of the therapeutic action of these drugs.102 Furthermore, blockade of hippocampal neurogenesis has been reported to prevent the actions of antidepressants in behavioral models of depression.134 In addition to antidepressant drugs, electroconvulsive therapy (ECT) and exercise-treatments known to be effective in decreasing depressive symptoms-also facilitate hippocampal neurogenesis.135,136 These effects could occur via alterations in cytokines, as antidepressants are reported to decrease levels of proinflammatory cytokines137 and, in fact, such effects may be necessary for antidepressant action.