Preclinical pharmacology of milnacipran

Milnacipran (Ixel) is a new antidepressant which has been developed for its selective inhibition of both serotonin and noradrenaline reuptake and its lack of affinity for neurotransmitter receptors. It inhibits virtually equipotently the reuptake of serotonin and noradrenaline both in vitro and in vivo, as demonstrated by the antagonism of centrally acting monoamine displacers. It has no effect on dopamine reuptake. In addition, milnacipran has been shown by intracerebral microdialysis to increase the extracellular levels of both serotonin and noradrenaline after acute administration. Milnacipran is devoid of interactions at any known neurotransmitter receptor or ion channel. In particular, and unlike tricyclic antidepressants, it does not act at noradrenergic, muscarinic or histaminergic receptors. Contrary to tricyclic antidepressants, chronic administration of milnacipran does not modify beta-adrenoceptor binding or second messenger function. Milnacipran is active on various animal models of depression such as the forced swimming test in the mouse, learned helplessness in the rat and the olfactory bulbectomized rat model. This pharmacological profile, associated with an excellent bioavailability in man, was predicted to be that required for a powerful and well-tolerated antidepressant. Subsequent clinical development has shown this prediction to be well founded.