Clinical data
Trade namesFetzima
Routes of
By mouth (capsules)
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding22%[2]
MetabolismHepatic (primarily by CYP3A4)[3]
Elimination half-life12 hours[3]
  • (1S,2R)-2-(Aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide
CAS Number
PubChem CID
Chemical and physical data
Molar mass246.354 g·mol−1
3D model (JSmol)
  • CCN(CC)C(=O)[C@]1(C[C@H]1CN)C2=CC=CC=C2
  • InChI=1S/C15H22N2O/c1-3-17(4-2)14(18)15(10-13(15)11-16)12-8-6-5-7-9-12/h5-9,13H,3-4,10-11,16H2,1-2H3/t13-,15+/m0/s1 ☒N
 ☒NcheckY (what is this?)  (verify)

Levomilnacipran (brand name Fetzima) is an antidepressant which was approved in the United States in 2013 for the treatment of major depressive disorder (MDD) in adults.[1] It is the levorotatory enantiomer of milnacipran, and has similar effects and pharmacology, acting as a serotonin–norepinephrine reuptake inhibitor (SNRI).[4][5]

Medical uses

A bottle of Fetzima.
A bottle of Fetzima.


The FDA approved levomilnacipran for the treatment of major depressive disorder based on the results of one 10-week phase II and four 8-week phase III clinical trials. Four of the five trials demonstrated a statistically significant superiority to placebo as measured by the Montgomery–Åsberg Depression Rating Scale. Superiority to placebo was also demonstrated by improvement in the Sheehan Disability Scale.

Side effects

Side effects seen more often with levomilnacipran than with placebo in clinical trials included nausea, dizziness, sweating, constipation, insomnia, increased heart rate and blood pressure, urinary hesitancy, erectile dysfunction and delayed ejaculation in males, vomiting, tachycardia, and palpitations.[6][7]



Relative to other SNRIs, levomilnacipran, as well as milnacipran, differ in that they are much more balanced reuptake inhibitors of serotonin and norepinephrine.[8][9][10] To demonstrate, the serotonin:norepinephrine ratios of SNRIs are as follows: venlafaxine = 30:1, duloxetine = 10:1, desvenlafaxine = 14:1, milnacipran = 1.6:1, and levomilnacipran = 1:2.[8] The clinical implications of more balanced elevations of serotonin and norepinephrine are unclear,[8] but may include improved effectiveness, though also increased side effects.[9][10][11]

Levomilnacipran is selective for the serotonin and norepinephrine transporters, lacking significant affinity for over 23 off-target sites.[12] However, it does show some affinity for the dizocilpine (MK-801/PCP) site of the NMDA receptor (Ki = 1.7 μM), and has been found to inhibit NR2A and NR2B subunit-containing NMDA receptors with respective IC50 values of 5.62 and 4.57 μM.[12] As such, levomilnacipran is an NMDA receptor antagonist at high concentrations.[12]

Levomilnacipran has recently been found to act as an inhibitor of beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1), which is responsible for β-amyloid plaque formation, and hence may be a potentially useful drug in the treatment of Alzheimer's disease.[13]


Levomilnacipran has a high oral bioavailability of 92% and a low plasma protein binding of 22%.[1][2] It is metabolized in the liver by the cytochrome P450 enzyme CYP3A4,[3] thereby making the medication susceptible to grapefruit-drug interactions. The drug has an elimination half-life of approximately 12 hours, allowing for once-daily administration.[3] Levomilnacipran is excreted in urine.[3]


Levomilnacipran was developed by Forest Laboratories and Pierre Fabre Group, and was approved by the Food and Drug Administration in July 2013.[6]


  1. ^ a b c "Fetzima (levomilnacipran) Extended-Release Capsules, for Oral Use. Full Prescribing Information". Forest Pharmaceuticals, Inc. Subsidiary of Forest Laboratories, Inc. St. Louis, MO 63045 USA. July 2014. Retrieved 2 September 2016.
  2. ^ a b Alan F. Schatzberg; Charles B. Nemeroff (10 May 2017). The American Psychiatric Association Publishing Textbook of Psychopharmacology. American Psychiatric Pub. pp. 533–. ISBN 978-1-61537-122-8.
  3. ^ a b c d e f Stephen M. Stahl (31 March 2017). Prescriber's Guide: Stahl's Essential Psychopharmacology. Cambridge University Press. pp. 373–376. ISBN 978-1-108-22874-9.
  4. ^ "Pierre Fabre Medicament and Forest Laboratories to Collaborate on Development and Commercialization of F2695 for Depression - FierceBiotech".
  5. ^ Deprez D, Chassard D, Baille P, Mignot A, Ung HL, Puozzo C (1998). "Which bioequivalence study for a racemic drug? Application to milnacipran". European Journal of Drug Metabolism and Pharmacokinetics. 23 (2): 166–71. doi:10.1007/bf03189334. PMID 9725476. S2CID 24621735.
  6. ^ a b Citrome L (November 2013). "Levomilnacipran for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antidepressant--what is the number needed to treat, number needed to harm and likelihood to be helped or harmed?". Int. J. Clin. Pract. 67 (11): 1089–104. doi:10.1111/ijcp.12298. PMID 24016209. S2CID 205185145.
  7. ^ Sambunaris A, Bose A, Gommoll CP, Chen C, Greenberg WM, Sheehan DV (February 2014). "A phase III, double-blind, placebo-controlled, flexible-dose study of levomilnacipran extended-release in patients with major depressive disorder". J Clin Psychopharmacol. 34 (1): 47–56. doi:10.1097/JCP.0000000000000060. PMC 4047313. PMID 24172209.
  8. ^ a b c Sansone RA, Sansone LA (March 2014). "Serotonin norepinephrine reuptake inhibitors: a pharmacological comparison". Innov Clin Neurosci. 11 (3–4): 37–42. PMC 4008300. PMID 24800132.
  9. ^ a b Saraceni MM, Venci JV, Gandhi MA (December 2013). "Levomilnacipran (Fetzima): A New Serotonin-Norepinephrine Reuptake Inhibitor for the Treatment of Major Depressive Disorder". J Pharm Pract. 27 (4): 389–395. doi:10.1177/0897190013516504. PMID 24381243. S2CID 41502983.
  10. ^ a b Kasper S, Pail G (2010). "Milnacipran: a unique antidepressant?". Neuropsychiatr Dis Treat. 6 (Suppl I): 23–31. doi:10.2147/NDT.S11777. PMC 2938282. PMID 20856597.
  11. ^ Bradley AJ, Lenox-Smith AJ (August 2013). "Does adding noradrenaline reuptake inhibition to selective serotonin reuptake inhibition improve efficacy in patients with depression? A systematic review of meta-analyses and large randomised pragmatic trials". J. Psychopharmacol. (Oxford). 27 (8): 740–58. doi:10.1177/0269881113494937. PMID 23832963. S2CID 36890464.
  12. ^ a b c Hair P, Cameron F, Garnock-Jones KP (2013). "Levomilnacipran extended release: first global approval". Drugs. 73 (14): 1639–45. doi:10.1007/s40265-013-0116-1. PMID 24000002. S2CID 965954.
  13. ^ Rizvi SM, Shaikh S, Khan M, Biswas D, Hameed N, Shakil S (2014). "Fetzima (levomilnacipran), a drug for major depressive disorder as a dual inhibitor for human serotonin transporters and beta-site amyloid precursor protein cleaving enzyme-1". CNS Neurol Disord Drug Targets. 13 (8): 1427–31. doi:10.2174/1871527313666141023145703. PMID 25345508.