Effectiveness of the Norepinephrine and Serotonin Reuptake Inhibitor Levomilnacipran in Healthy Males

Levomilnacipran (Fetzima) is the active enantiomer of milnacipran (Ixel, Savella) for norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) reuptake. It has an approximate eight-fold greater affinity for the human NE transporter than for the 5-HT transporter. This signifies that the NE transporter may be engaged to a much greater degree than the 5-HT transporter at various doses, especially at lower regimens. As such, levomilnacipran represents the mirror antidepressant medication of venlafaxine and duloxetine since at their minimal effective doses, these medications are selective inhibitors of 5-HT reuptake and it is not until daily regimens are doubled or tripled that the NE transporter gets engaged.

Levomilnacipran is effective clinically in patients with major depressive disorder (MDD) at doses ranging between 40 and 120 mg/day. Given this wide effective dose range, it appears essential to determine the in vivo potency of levomilnacipran and the dose at which it starts inhibiting 5-HT in relation to NE reuptake in humans.

The current investigators have studied the NE reuptake blocking properties of antidepressants in both healthy volunteers and patients with depression using tyramine pressor tests. This peripheral model of adrenergic function involves administration of repeated intravenous injections of tyramine and measurement of transient increases in systolic blood pressure (SBP) that occur after a tyramine load. This approach has led to dose-dependent SBP increases that are reliably reproduced one week apart in healthy volunteers who received placebo which supports the use of the tyramine pressor test to assess the functional capacity of different medication regimens to inhibit NE reuptake at steady state levels. Serotonin reuptake has been extensively studied in human participants using the blood platelet model. In this assay, whole blood 5-HT and/or platelet content is determined before and after giving reuptake inhibitors. Since the 5-HT transporter is similar on 5-HT neurons in the brain and on platelets, the degree of 5-HT depletion in the blood can be used as a measure of 5-HT reuptake blockade in the brain. Together, these experimental approaches will identify the potency of levomilnacipran for NE and 5-HT reuptake inhibition.

The purpose of this study is to determine the potency of levomilnacipran required to inhibit NE and 5-HT reuptake in healthy male participants across the effective dose range of the medication (40-120 mg/day).

Participants Healthy male participants will receive escalating doses of levomilnacipran, duloxetine, or placebo every 4-7 days throughout a 14-23 day period. The tyramine pressor procedure will be used to identify the dose at which these medications inhibit norepinephrine reuptake. Serotonin reuptake inhibition will be estimated from whole blood serotonin concentrations. Tyramine testing and blood draws will occur at baseline (prior to medication administration) and 4 days after each dose escalation.