levomilnacipran

File:Fetzima 1.jpg

Levomilnacipran is indicated for the treatment of major depressive disorder in adults.

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.{{cite journal | vauthors = Sambunaris A, Bose A, Gommoll CP, Chen C, Greenberg WM, Sheehan DV | title = A phase III, double-blind, placebo-controlled, flexible-dose study of levomilnacipran extended-release in patients with major depressive disorder | journal = Journal of Clinical Psychopharmacology | volume = 34 | issue = 1 | pages = 47–56 | date = February 2014 | pmid = 24172209 | pmc = 4047313 | doi = 10.1097/JCP.0000000000000060 }}

Relative to other serotonin and norepinephrine reuptake inhibitors, levomilnacipran, as well as milnacipran, differ in that they are much more balanced reuptake inhibitors of serotonin and norepinephrine.{{cite journal | vauthors = Sansone RA, Sansone LA | title = Serotonin norepinephrine reuptake inhibitors: a pharmacological comparison | journal = Innovations in Clinical Neuroscience | volume = 11 | issue = 3–4 | pages = 37–42 | date = March 2014 | pmid = 24800132 | pmc = 4008300 }}{{cite journal | vauthors = Saraceni MM, Venci JV, Gandhi MA | title = Levomilnacipran (Fetzima): A New Serotonin-Norepinephrine Reuptake Inhibitor for the Treatment of Major Depressive Disorder | journal = Journal of Pharmacy Practice | volume = 27 | issue = 4 | pages = 389–395 | date = August 2014 | pmid = 24381243 | doi = 10.1177/0897190013516504 | s2cid = 41502983 }}{{cite journal | vauthors = Kasper S, Pail G | title = Milnacipran: a unique antidepressant? | journal = Neuropsychiatric Disease and Treatment | volume = 6 | issue = Suppl I | pages = 23–31 | date = September 2010 | pmid = 20856597 | pmc = 2938282 | doi = 10.2147/NDT.S11777 | doi-access = free }} 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. The clinical implications of more balanced elevations of serotonin and norepinephrine are unclear, but may include improved effectiveness, though also increased side effects.{{cite journal | vauthors = Bradley AJ, Lenox-Smith AJ | title = 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 = Journal of Psychopharmacology | volume = 27 | issue = 8 | pages = 740–758 | date = August 2013 | pmid = 23832963 | doi = 10.1177/0269881113494937 | s2cid = 36890464 }}

Levomilnacipran is selective for the serotonin and norepinephrine transporters, lacking significant affinity for over 23 off-target sites.{{cite journal | vauthors = Hair P, Cameron F, Garnock-Jones KP | title = Levomilnacipran extended release: first global approval | journal = Drugs | volume = 73 | issue = 14 | pages = 1639–1645 | date = September 2013 | pmid = 24000002 | doi = 10.1007/s40265-013-0116-1 | s2cid = 965954 }} However, it does show some affinity for the dizocilpine (MK-801/{{abbrlink|PCP|phencyclidine}}) site of the NMDA receptor (K_i = 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. As such, levomilnacipran is an NMDA receptor antagonist at high concentrations.

Levomilnacipran has a high oral bioavailability of 92% and a low plasma protein binding of 22%.{{cite book| vauthors = Norris S, Blier P | chapter = Duloxetine, Milnacipran, and Levomilnacipran | veditors = Schatzberg AF, Nemeroff CB |title=The American Psychiatric Association Publishing Textbook of Psychopharmacology| chapter-url = https://books.google.com/books?id=v9wnDwAAQBAJ&pg=PA533 |date=10 May 2017 |publisher=American Psychiatric Pub |isbn=978-1-61537-122-8 |pages=533– }} It is metabolized in the liver by the cytochrome P450 enzyme CYP3A4,{{cite book| vauthors = Stahl SM |title=Prescriber's Guide: Stahl's Essential Psychopharmacology |url= https://books.google.com/books?id=9hssDwAAQBAJ&pg=PA373 |date=31 March 2017|publisher=Cambridge University Press|isbn=978-1-108-22874-9|pages=373–376}} 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. Levomilnacipran is excreted in urine.

Levomilnacipran was developed by Forest Laboratories and Pierre Fabre Group, and was approved by the US Food and Drug Administration in July 2013.{{cite journal | vauthors = Citrome L | title = 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? | journal = International Journal of Clinical Practice | volume = 67 | issue = 11 | pages = 1089–1104 | date = November 2013 | pmid = 24016209 | doi = 10.1111/ijcp.12298 | s2cid = 205185145 }} The FDA approved levomilnacipran for treating major depressive disorder. The approval was based on the results of five clinical trials. The trials included one 10-week phase II and four 8-week phase III. 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.

Levomilnacipran has 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.{{cite journal | vauthors = Rizvi SM, Shaikh S, Khan M, Biswas D, Hameed N, Shakil S | title = 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 | journal = CNS & Neurological Disorders Drug Targets | volume = 13 | issue = 8 | pages = 1427–1431 | year = 2014 | pmid = 25345508 | doi = 10.2174/1871527313666141023145703 }}

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