Ixel was launched in France as an antidepressant. There are several
synthetic routes, the shortest of which is five steps using benzyl cyanide as the starting
material. It is a specific serotonin and noradrenaline reuptake inhibitor (SNRI). This
dual mechanism of action makes it superior to selective serotonin reuptake inhibitors
(SSRI) like fluoxetine and fluvoxamine. Ixel has no significant effect on postsynaptic
receptors, very limited effect on cardiac function, and no quinidine-like arrhythmal
effects. It has a good side effect profile with lower incidence of anticholinergic-like
side effects, less sedation due to histamine H1-receptor binding, and a lack of α1-
adrenoceptor antagonism. Ixel has a short half-life (7 hr) with no active metabolites. It
is not metabolized by CYP450 therefore drug interaction is unlikely. It is superior in
the treatment of serious depression with no need to titrate drug dose.
ChEBI: (1R,2S)-2-(aminomethyl)-N,N-diethyl-1-phenyl-1-cyclopropanecarboxamide is a member of acetamides.
Milnacipran selectively inhibits the reuptake of 5-HT (selectivity ratio, 9) at the presynaptic membrane site,
thus increasing the concentration of 5-HT in the synaptic cleft. Although milnacipran is not a TCA, its
mechanism of action is similar to that of imipramine, and its binding and reuptake inhibition profile more
closely resembles that of the TCAs. Milnacipran has weak affinity for adrenergic, muscarinic, and H1
receptors and, therefore, is expected to be devoid of the prominent side effects observed for the TCAs. In
clinical studies, milnacipran showed antidepressant efficacy similar to that of TCAs and SSRIs.
In humans, milnacipran distinguishes itself from many other antidepressants by its simple pharmacokinetics. It
is rapidly absorbed, with a high oral bioavailability, and it exhibits linear pharmacokinetics over a dose range
of 25 to 200 mg/day. It circulates in the blood and distributes in the body principally as
unmetabolized drug. Steady-state plasma levels are reached within 32 to 48 hours after twice-daily oral
administration, and its metabolism does not involve the CYP enzyme system. Approximately 50% of the dose
is excreted in urine as unmetabolized drug, and another 14% is excreted as its N-glucuronide conjugate. The
remaining eliminated drug is composed of conjugated Phase I inactive metabolites. Because the
unmetabolized drug is the only compound responsible for the activity of milnacipran, no dosage adjustment is
needed in patients presenting liver impairment.
(±)-Milnacipran is the ci s-aminomethyl derivative of phenylcyclopropanecarboxamide that acts by
inhibiting both NE and 5-HT reuptake. It is structurally different from the other NSRIs and currently is only
available in Europe as a racemic mixture, with both enantiomers exhibiting antidepressant activity.
Substituting the aminomethyl group of milnacipran with an aminopropyl gives a milnacipran homologue that
exhibits antidepressant activity as a potent N-methyl-D-aspartate (NMDA) receptor antagonist. A glutamate
hypothesis is being investigated as an alternative mechanism of depression.
Milnacipran has proven to be a very safe drug, with an adverse-event profile clearly superior to that of TCAs
and, to a certain extent, that of SSRIs. Only approximately 10% of patients experience side effects, and only
dysuria occurred more frequently (2%) with milnacipran than with TCAs or SSRIs. Milnacipran therefore
appears to be an antidepressant with a very favorable benefit:risk ratio, although with a slower onset of
action than the TCAs.
