Milnacipran: a unique antidepressant?

Abstract

Tricyclic antidepressants (TCAs) are among the most effective antidepressants available, although their poor tolerance at usual recommended doses and toxicity in overdose make them difficult to use. While selective serotonin reuptake inhibitors (SSRIs) are better tolerated than TCAs, they have their own specific problems, such as the aggravation of sexual dysfunction, interaction with coadministered drugs, and for many, a discontinuation syndrome. In addition, some of them appear to be less effective than TCAs in more severely depressed patients. Increasing evidence of the importance of norepinephrine in the etiology of depression has led to the development of a new generation of antidepressants, the serotonin and norepinephrine reuptake inhibitors (SNRIs). Milnacipran, one of the pioneer SNRIs, was designed from theoretic considerations to be more effective than SSRIs and better tolerated than TCAs, and with a simple pharmacokinetic profile. Milnacipran has the most balanced potency ratio for reuptake inhibition of the two neurotransmitters compared with other SNRIs (1:1.6 for milnacipran, 1:10 for duloxetine, and 1:30 for venlafaxine), and in some studies milnacipran has been shown to inhibit norepinephrine uptake with greater potency than serotonin (2.2:1). Clinical studies have shown that milnacipran has efficacy comparable with the TCAs and is superior to SSRIs in severe depression. In addition, milnacipran is well tolerated, with a low potential for pharmacokinetic drug-drug interactions. Milnacipran is a first-line therapy suitable for most depressed patients. It is frequently successful when other treatments fail for reasons of efficacy or tolerability.

Keywords: SNRI; antidepressant efficacy; milnacipran; tolerability.

Figure 1

Relation between neurotransmitters and symptoms of depression. Adapted from Nutt.

Figure 2

Selectivity of different serotonin and norepinephrine reuptake inhibitors for the monoamine transporters. The segments represent the selectivity for the human norepinephine and serotonin (5-HT) transporters calculated according to data from Koch et al.

Figure 3

Antidepressant response and psychomotor retardation. Retardation score was the score of item 8 on the Hamilton Depression Rating Scale (slowness of thought and speech, impaired ability to concentrate, decreased motor activity). Dark grey columns = milnacipran; light grey columns = paroxetine. Figure drawn from data in Sechter et al. *P < 0.05.

Figure 4

Meta-analysis of 93 studies comparing dual action antidepressants and selective serotonin reuptake inhibitorsinvolving 17,036 patients. Columns show the relative probability of response compared with selective serotonin reuptake inhibitors. Figure drawn from data in Papakostas et al. Abbreviations: venla, venlafaxine; dulox, duloxetine; milna, milnacipran; mirta, mirtazapine; mians, mianserin; moclo, moclobemide.