Current treatments for depression are inadequate for many patients, and different therapies have been proposed to ameliorate the clinical responses of antidepressant drugs through augumentation or combination strategies. Another achievement in the development of new treatments is to reduce the latency of clinical effect of antidepressant drugs known to be characterized by 4−6 weeks lag phase. Evidence has accumulated suggesting that major depression is associated with dysfunction of inflammatory mediators and that psychiatric symptoms may occur during inflammatory diseases. Moreover antidepressants show an anti-inflammatory action possibly related to their clinical efficacy. In fact, an improvement in psychiatric symptoms has been recently reported in patients treated with anti-inflammatory drugs for other indications. These data imply that inflammation may be involved in the pathogenesis of depression and that anti-inflammatory drugs may be used as an adjunctive therapy. Among the anti-inflammatory drugs the Acetylsalicylic acid has been shown to act on the brain serotonergic system and to have a neuroprotective effect toward brain damage. Aim of the present study was to evaluate the effects of combined treatment fluoxetine (FLX) plus acetylsalicylic acid (ASA) in a behavioural model of depression: the chronic escape deficit. 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. In this model, FLX alone needs to be administered for at least 3 weeks in order to revert this condition. Our results showed that ASA (45 mg/kg) did not possess antidepressant properties in the chronic escape deficit model at any time tested. A combined treatment of FLX (5 mg/kg) and ASA (45 mg/kg) 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. In the same experimental condition the effect of FLX (5 mg/kg) was significant only at 21 days, as previously demonstrated by other groups. The exact nature of the mechanisms underlying the above behavioural effects are still unknown, nevertheless several hypotheses can be formulated. Moreover, because a role for the neurotrophin BDNF was proposed in the clinical response to antidepressant treatment, we have determined the effect of combined treatment FLX plus ASA on hippocampal BDNF mRNA and protein in the same behavioural model. Ours data demonstrated that the hippocampal levels of BDNF mRNA were significantly increased with respect to control groups (naive and stressed) only in the animals responding (number of escape 10 out of 30 trials) to the combined treatment. Further biochemical and genetic researches could help to clarify the targets of action of the combined treatment FLX plus ASA for the development of more active and faster molecules.
Behavioural and molecular effects of the combined treatment fluoxetine plus acetylsalicylic acid in a rat model of depression / Alboni, Silvia; Capone, Giacomo; Benatti, Cristina; Tascedda, Fabio; Blom, Johanna Maria Catharina; Mendlewicz, J; Brunello, Nicoletta. - In: EUROPEAN NEUROPSYCHOPHARMACOLOGY. - ISSN 0924-977X. - STAMPA. - 16:(2006), pp. S339-S339. (Intervento presentato al convegno 19th Congress of the European-College-of-Neuropsychopharmacology tenutosi a Paris, FRANCE nel 16-20 September 2006) [10.1016/S0924-977X(06)70383-2].