SNRI antidepressant drug
Pharmaceutical compound
Levomilnacipran , sold under the brand nameFetzima , is anantidepressant , used for the treatment ofmajor depressive disorder in adults.[ 4] levorotatory enantiomer ofmilnacipran , and has similar effects andpharmacology , acting as aserotonin–norepinephrine reuptake inhibitor .[ 7] [ 8]
Levomilnacipran was approved for medical use in the United States in July 2013.[ 9]
A bottle of Fetzima. Levomilnacipran isindicated for the treatment ofmajor depressive disorder in adults.[ 4]
Side effects seen more often with levomilnacipran than withplacebo in clinical trials includednausea ,dizziness ,sweating ,constipation ,insomnia , increasedheart rate andblood pressure ,urinary hesitancy ,erectile dysfunction anddelayed ejaculation in males,vomiting ,tachycardia , andpalpitations .[ 10] [ 11]
Relative to other serotonin and norepinephrine reuptake inhibitors, levomilnacipran, as well as milnacipran, differ in that they are much more balancedreuptake inhibitors ofserotonin andnorepinephrine .[ 12] [ 13] [ 14] venlafaxine = 30:1,duloxetine = 10:1,desvenlafaxine = 14:1, milnacipran = 1.6:1, and levomilnacipran = 1:2.[ 12] [ 12] [ 13] [ 14] [ 15]
Levomilnacipran isselective for theserotonin andnorepinephrine transporters , lacking significantaffinity for over 23 off-target sites .[ 16] dizocilpine (MK-801/PCP Tooltip phencyclidine ) site of theNMDA receptor (Ki = 1.7 μM), and has been found to inhibitNR2A andNR2B subunit -containing NMDA receptors with respectiveIC50 values of 5.62 and 4.57 μM.[ 16] NMDA receptor antagonist at high concentrations.[ 16]
Levomilnacipran has a highoral bioavailability of 92% and a lowplasma protein binding of 22%.[ 4] [ 5] metabolized in theliver by thecytochrome P450 enzyme CYP3A4 ,[ 6] grapefruit-drug interactions . The drug has anelimination half-life of approximately 12 hours, allowing for once-daily administration.[ 6] excreted inurine .[ 6]
Levomilnacipran was developed byForest Laboratories andPierre Fabre Group , and was approved by the USFood and Drug Administration in July 2013.[ 9] [ 10] clinical trials . The trials included one 10-weekphase II and four 8-weekphase III . Four of the five trials demonstrated a statistically significant superiority to placebo as measured by theMontgomery–Åsberg Depression Rating Scale . Superiority to placebo was also demonstrated by improvement in theSheehan Disability Scale .
Levomilnacipran has been found to act as aninhibitor ofbeta-site amyloid precursor protein cleaving enzyme-1 (BACE-1), which is responsible forβ-amyloid plaque formation, and hence may be a potentially useful drug in the treatment ofAlzheimer's disease .[ 17]
^ Anvisa (31 March 2023)."RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese).Diário Oficial da União (published 4 April 2023).Archived from the original on 3 August 2023. Retrieved16 August 2023 .^ "Product monograph brand safety updates" .Health Canada . Retrieved3 April 2024 .^ "Health Canada New Drug Authorizations: 2015 Highlights" .Health Canada . Retrieved7 April 2024 .^a b c d e "Fetzima- levomilnacipran hydrochloride capsule, extended release; Fetzima- levomilnacipran hydrochloride kit" .DailyMed . 19 April 2024. Retrieved17 April 2025 .^a b Norris S, Blier P (10 May 2017)."Duloxetine, Milnacipran, and Levomilnacipran" . In Schatzberg AF, Nemeroff CB (eds.).The American Psychiatric Association Publishing Textbook of Psychopharmacology . American Psychiatric Pub. pp. 533–.ISBN 978-1-61537-122-8 ^a b c d e f Stahl SM (31 March 2017).Prescriber's Guide: Stahl's Essential Psychopharmacology 373– 376.ISBN 978-1-108-22874-9 ^ Myers C (22 December 2008)."Pierre Fabre Medicament and Forest Laboratories to Collaborate on Development and Commercialization of F2695 for Depression" .FierceBiotech . ^ 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– 171.doi :10.1007/bf03189334 .PMID 9725476 .S2CID 24621735 . ^a b "Drug Approval Package: Fetzima (levomilnacipran) Extended-Release Capsules NDA #204168" .U.S.Food and Drug Administration (FDA) . 14 March 2014. Archived fromthe original on 29 June 2015. Retrieved17 April 2025 .^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?".International Journal of Clinical Practice .67 (11):1089– 1104.doi :10.1111/ijcp.12298 .PMID 24016209 .S2CID 205185145 . ^ 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" .Journal of Clinical Psychopharmacology .34 (1):47– 56.doi :10.1097/JCP.0000000000000060 .PMC 4047313 PMID 24172209 . ^a b c Sansone RA, Sansone LA (March 2014)."Serotonin norepinephrine reuptake inhibitors: a pharmacological comparison" .Innovations in Clinical Neuroscience .11 (3– 4):37– 42.PMC 4008300 PMID 24800132 . ^a b Saraceni MM, Venci JV, Gandhi MA (August 2014). "Levomilnacipran (Fetzima): A New Serotonin-Norepinephrine Reuptake Inhibitor for the Treatment of Major Depressive Disorder".Journal of Pharmacy Practice .27 (4):389– 395.doi :10.1177/0897190013516504 .PMID 24381243 .S2CID 41502983 . ^a b Kasper S, Pail G (September 2010)."Milnacipran: a unique antidepressant?" .Neuropsychiatric Disease and Treatment .6 (Suppl I):23– 31.doi :10.2147/NDT.S11777 PMC 2938282 PMID 20856597 . ^ 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".Journal of Psychopharmacology .27 (8):740– 758.doi :10.1177/0269881113494937 .PMID 23832963 .S2CID 36890464 . ^a b c Hair P, Cameron F, Garnock-Jones KP (September 2013). "Levomilnacipran extended release: first global approval".Drugs .73 (14):1639– 1645.doi :10.1007/s40265-013-0116-1 .PMID 24000002 .S2CID 965954 . ^ 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 & Neurological Disorders Drug Targets .13 (8):1427– 1431.doi :10.2174/1871527313666141023145703 .PMID 25345508 .
SSRIs Tooltip Selective serotonin reuptake inhibitors SNRIs Tooltip Serotonin–norepinephrine reuptake inhibitors NRIs Tooltip Norepinephrine reuptake inhibitors NDRIs Tooltip Norepinephrine–dopamine reuptake inhibitors NaSSAs Tooltip Noradrenergic and specific serotonergic antidepressants SARIs Tooltip Serotonin antagonist and reuptake inhibitors SMS Tooltip Serotonin modulator and stimulators Others
TCAs Tooltip Tricyclic antidepressants TeCAs Tooltip Tetracyclic antidepressants Others
Non-selective MAOA Tooltip Monoamine oxidase A -selectiveMAOB Tooltip Monoamine oxidase B -selective
AMPAR Tooltip α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor KAR Tooltip Kainate receptor NMDAR Tooltip N-Methyl-D-aspartate receptor
DAT Tooltip Dopamine transporter (DRIs Tooltip Dopamine reuptake inhibitors )
NET Tooltip Norepinephrine transporter (NRIs Tooltip Norepinephrine reuptake inhibitors )
Others: Antihistamines (e.g.,brompheniramine ,chlorphenamine ,pheniramine ,tripelennamine )Antipsychotics (e.g.,loxapine ,ziprasidone )Arylcyclohexylamines (e.g.,ketamine ,phencyclidine )Dopexamine Ephenidine Ginkgo biloba Indeloxazine Nefazodone Opioids (e.g.,desmetramadol ,methadone ,pethidine (meperidine) ,tapentadol ,tramadol ,levorphanol )
SERT Tooltip Serotonin transporter (SRIs Tooltip Serotonin reuptake inhibitors )
Others: A-80426 Amoxapine Antihistamines (e.g.,brompheniramine ,chlorphenamine ,dimenhydrinate ,diphenhydramine ,mepyramine (pyrilamine) ,pheniramine ,tripelennamine )Antipsychotics (e.g.,loxapine ,ziprasidone )Arylcyclohexylamines (e.g.,3-MeO-PCP ,esketamine ,ketamine ,methoxetamine ,phencyclidine )Cyclobenzaprine Delucemine Dextromethorphan Dextrorphan Efavirenz Hypidone Medifoxamine Mesembrine Mifepristone MIN-117 (WF-516) N-Me-5-HT Opioids (e.g.,dextropropoxyphene ,methadone ,pethidine (meperidine) ,levorphanol ,tapentadol ,tramadol )Roxindole
VMATs Tooltip Vesicular monoamine transporters Others
Phenethylamines Amphetamines Phentermines Cathinones Phenylisobutylamines (and further-extended) Catecholamines (and close relatives) Cyclized
Phenylalkylpyrrolidines 2-Benzylpiperidines (phenidates ) Phenylmorpholines (phenmetrazines) Phenyloxazolamines (aminorexes) Isoquinolines andtetrahydroisoquinolines 2-Aminoindanes 2-Aminotetralins Others / unsorted 1-Aminomethylindanes (e.g.,2CB-Ind ,AMMI ,bromojimscaline ,jimscaline )2-ADN 2-Benzhydrylpyrrolidine 2C-B-5-hemiFLY-α6 (BNAP) 2C-B-PYR 2CBecca 2CB7 2CJP 2CLisaB 2CLisaH 3-Benzazepines (e.g.,fenoldopam ,lorcaserin ,7-chlorolorcaserin ,SCHEMBL5334361 )3-Benzhydrylmorpholine 3-Phenylpiperidines (e.g.,3-phenylpiperidine ,3-PPP ,OSU-6162 (PNU-96391) ,LPH-5 ,LPH-48 ,Z3517967757 (Z7757) )6-AB AL-1095 Aminochromes (e.g.,adrenochrome ,adrenolutin )Benzocyclobutenes (e.g.,2CBCB-NBOMe ,bromotomscaline ,S33005 ,TCB-2 ,tomscaline )Benzoxepins (e.g.,BBOX ,IBOX ,TFMBOX )Butyltolylquinuclidine Camfetamine Cypenamine (trans -2-phenylcyclopentylamine) Diphenidine Diphenylprolinol DMBMPP Ergolines (e.g.,LSD )Fencamfamin GYKI-52895 HDMP-29 Ivabradine Methoxphenidine Methylmorphenate Milnacipran MT-45 2-Naphthylamine Org 6582 Partial ergolines (e.g.,NDTDI ,RU-27849 ,DEIMDHPCA ,DEMPDHPCA ,DEMPDHPCA-2C-D ,RU-27251 )PF-592,379 Phenylcyclopropylamines (e.g.,DMCPA ,TMT ,tranylcypromine )Phenylpiracetams (e.g.,phenylpiracetam ,MRZ-9547 ,RGPU-95 )Pyridopyrroloquinoxalines (e.g.,lumateperone ,deulumateperone ,IHCH-7079 ,IHCH-7086 ,IHCH-7113 ,ITI-1549 )Tetrahydrobenzopyranylamines (e.g.,CT-5126 )Tolazoline Tricyclics (e.g.,AMDA ,AMDH ,benzoctamine ,dizocilpine ,SpAMDA )ZC-B
Related compounds 2-Furylethylamine 2-Pyrrolylethylamine 3-Pyrrolylethylamine 3-Pyrrolylpropylamine 2-Tetrahydrofurylethylamine 4-Benzylpiperidine 7-AB Alkylamines (e.g.,1,3-DMBA Tooltip 1,3-dimethylbutylamine ,1,4-DMAA Tooltip 1,4-dimethylamylamine ,heptaminol ,iproheptine ,isometheptene ,methylhexanamine/ 1,3-DMAA ,octodrine ,oenethyl ,tuaminoheptane )Benzylamines (e.g.,benzylamine ,α-methylbenzylamine ,MDM1EA ,ALPHA ,M-ALPHA ,pargyline )Benzylpiperazines (e.g.,benzylpiperazine ,MDBZP ,fipexide )Cyclohexylaminopropanes (e.g.,propylhexedrine ,norpropylhexedrine )Cyclopentylaminopropanes (e.g.,isocyclamine ,cyclopentamine )Phenoxyethylamines (e.g.,3,4,5-trimethoxyphenoxyethylamine ,CT-4719 ,ORG-37684 )Phenylalkenylamines (e.g.,phenylbutenamine )Phenylalkynylamines (e.g.,phenylbutynamine )Phenylpiperazines (e.g.,1-phenylpiperazine ,mCPP Tooltip meta-chlorophenylpiperazine ,TFMPP Tooltip trifluoromethylphenylpiperazine ,oMPP Tooltip ortho-methylphenylpiperazine ,pFPP Tooltip para-fluorophenylpiperazine ,pMeOPP Tooltip para-methoxyphenylpiperazine )Phenylpropylamines (e.g.,phenylpropylamine ,homo-MDA ,homo-MDMA )Thienylaminopropanes (thiopropamines) (e.g.,thiopropamine ,methiopropamine ,thiothinone )
N
Y (what is this?) (verify)
Media related toLevomilnacipran at Wikimedia Commons
