Milnacipran: the most noradrenergic SNRI
Of the four SNRIs currently available, milnacipran is the most noradrenergic in terms of its selectivity for the inhibition of the reuptake of NE and 5-HT (Figure 3).33,34 There is neurochemical and neurophysiological evidence that milnacipran acts by increasing NE neurotransmission. A study investigating the influence of NE transporter polymorphism (NET-T182C polymorphism) on the antidepressant effect of milnacipran35 found a significant difference (P < 0.03) in response, depending on the genotype of the patients (T/T 76.7% responders; T/C 57.8% responders; C/C 20% responders). Similarly, antidepressant response with milnacipran was sensitive to NET-G1287A polymorphism, with the A/A genotype being associated with a slower onset of therapeutic response.35 In contrast, there was no influence of 5-HTT polymorphisms on the antidepressant response to milnacipran.35 These results suggest that the effect of milnacipran on the NE transporter is fundamental to its action.