New combination therapies from animal to human

Evidence has accumulated suggesting that major depression is associated with dysfunction of inflammatory mediators. Antidepressants interfere with the synthesis and release of cytokines and do not exert behavioral effects in animal models of depression when hippocampal neurogenesis is blocked, a phenomenon which is occurring in the presence of inflammation. The anti-inflammatory drug acetylsalicylic acid (ASA), besides inhibiting the cyclooxigenase pathway, interacts with central serotonergic system, by increasing serotonin levels in cortex and reducing the density of different serotonin receptor subtypes. These neurochemical effects suggest a role of ASA in the treatment of depression. Therefore we studied the effect of ASA and fluoxetine combined treatment in a behavioral model of depression. The chronic escape deficit model is based on the modified reactivity of rats to external stimuli induced by exposure to unavoidable stress and allows evaluating the capacity of a treatment to revert the condition of escape deficit. Any kind of antidepressant drug needs to be administered for at least 3 weeks in order to revert this condition. The combined treatment of fluoxetine and ASA completely reverted the condition of escape deficit as early as after 7 days, the effect being already partially present after 4 days. The effect was maintained after 14 and 21 days of treatment. ASA alone was ineffective at any time tested and the effect of fluoxetine was significant only at 21 days. Given these preclinical results, an open clinical study has been started using the combination SSRI-ASA in treatment resistant depressed patients. Preliminary results suggest a potential accelerating effect of ASA in combination to SSRI.