CNS Drug Reviews

Selective serotonin reuptake inhibitors (SSRIs) were developed with the idea of removing from the pharmacological profile of tricyclic antidepressants (TCA) all of the activities which were thought to be responsible for their adverse effects. Thus interactions with the muscarinic cholinergic receptor, the histamine receptor, and the α1 adrenoceptor were avoided. In addition, the ability to inhibit the reuptake of norepinephrine was also excluded from the mechanism of this new class of antidepressants, probably to eliminate potential cardiovascular effects. This strategy of selectivity has clearly been beneficial in terms of adverse effect rates, which are lower for SSRIs than for TCAs. In retrospect, however, the selectivity for a single monoamine was not the best strategy and tends to result in a lesser efficacy than that of TCAs, especially in severe or endogenous depression. This is suggested, for example, by the demonstration, in controlled studies that the TCA clomipramine is significantly superior to citalopram (10) or paroxetine (11) in endogenously depressed patients. General clinical opinion appears to confirm the findings of these trials. A recent survey of Swedish psychiatrists, for example, showed that 80% of those questioned considered that SSRIs were not equivalent to TCAs in severe depression (25). Milnacipran1 was thus developed as a new specific serotonin and norepinephrine reuptake inhibitor (SNRI) with the intention of providing greater antidepressant efficacy than the SSRIs without the side effects of the TCA (7). This article reviews the preclinical properties, pharmacokinetics, and principal clinical and safety data of milnacipran. CNS Drug Reviews Vol. 4, No. 2, pp. 137–148 © 1998 Neva Press, Branford, Connecticut