Acetylsalicylic acid accelerates the antidepressant effect of fluoxetine in a rat model of depression

Depression currently ranks fourth among the major causesof disability worldwide and by 2020, it is estimated thatunipolar major depression will rank second as a sourceof lost disability-adjusted life years (DALYs) worldwide(Murray and Lopez, 1997). To date however no singleagent is effective in all patients treated, probably due tothe different neurobiological alterations occurring for thedisorder and to individual differences in pharmacogeneticand pharmacodynamic parameters.Different therapies have been proposed to amelioratethe clinical responses of antidepressant drugs throughaugmentation or combination strategies.Another achievement in the development of newtreatments is to reduce the latency of clinical effect ofantidepressant drugs known to be characterized by 4-6weeks lag phase.Evidence has accumulated suggesting that majordepression is associated with dysfunction of inflammatorymediators and that psychiatric symptoms may occur duringinflammatory diseases. Moreover antidepressants show ananti-inflanmlatory action possibly related to their clinicalefficacy. In fact, an improvement in psychiatric symptomshas been recently reported in patients treated with antiinflammatorydrugs for other indications.These data imply that inflammation may be involved inthe pathogenesis of depression and that anti-inflanm~atorydrugs may be used as an adjunctive therapy.Among anti-inflammatory drugs acetylsalicylic acid(ASA) has been shown to act on the brain serotonergicsystem and to have a neuroprotective effect in vitro aswell as in vivo.Aim of the present study was to evaluate the effectsof combined treatment fluoxetine (FLX) plus ASA andASA alone in a behavioural model of depression:the chronic escape deficit (Gambarana et al., 2001).The chronic escape deficit model is based on themodified reactivity of rats to external stimuli inducedby exposure to unavoidable stress and allows evaluatingthe capacity of a treatment to revert the condition ofescape deficit. In this model, FLX alone needs to beadministered for at least 3 weeks in order to revert thiscondition.Our results showed that ASA (45 mg/kg) did not possessantidepressant properties in the chronic escape deficitmodel at any time tested. A combined treatment of FLX(5 mg/kg) and ASA (45 mg/kg) completely reverted thecondition of escape deficit as early as after 7 days, theeffect being already partially present after 4 days. Theeffect was maintained after 14 and 21 days of treatment.In the same experimental condition the effect of FLX(5 mg/kg) was significant only at 21 days, as previouslydemonstrated by other groups.The exact nature of the mechanisms underlying theabove behavioural effects are still unknown, neverthelessseveral hypotheses can be formulated. Further biochemicaland genetic researches could help to clarify the targets ofaction of the combined treatment FLX plus ASA for thedevelopment of more active and faster acting molecules.