Samidorphan was under development as a standalone medication for various indications but has been discontinued.[7]Buprenorphine/samidorphan for the treatment ofmajor depressive disorder was rejected by the USFood and Drug Administration (FDA) due to insufficient evidence of effectiveness, but remains in preregistration as of September 2021.[8] Development ofbaclofen/samidorphan has also been discontinued.[9]
It has attracted much more attention as part of thecombination product (buprenorphine/samidorphan), where samidorphan is combined with the mixedμ-opioid receptor (MOR) weakpartial agonist andκ-opioid receptor (KOR) antagonistbuprenorphine, as anantidepressant. Buprenorphine has shown antidepressant effects in some human studies, thought to be because of its antagonist effects at the KOR, but has not been further developed for this application because of its MOR agonist effects and consequentabuse potential. By combining buprenorphine with samidorphan to block the MOR agonist effects, the combination acts more like a selective KOR antagonist, and produces only antidepressant effects, without typical MOR effects such aseuphoria orsubstance dependence being evident.[12][13]
Samidorphan was also studied in combination witholanzapine, (olanzapine/samidorphan), for use inschizophrenia.[14] A Phase III study found that the addition of samidorphan to olanzapine significantly reduced weight gain compared to olanzapine alone,[15] and the combination was approved for the treatment of schizophrenia andbipolar disorder by the FDA in May 2021, under the brand name Lybalvi.[16][17]
^abTurncliff R, DiPetrillo L, Silverman B, Ehrich E (February 2015). "Single- and multiple-dose pharmacokinetics of samidorphan, a novel opioid antagonist, in healthy volunteers".Clinical Therapeutics.37 (2):338–348.doi:10.1016/j.clinthera.2014.10.001.PMID25456560.
^Hillemacher T, Heberlein A, Muschler MA, Bleich S, Frieling H (August 2011). "Opioid modulators for alcohol dependence".Expert Opinion on Investigational Drugs.20 (8):1073–1086.doi:10.1517/13543784.2011.592139.PMID21651459.S2CID43338618.
^Clinical trial numberNCT01366001 for "ALK33BUP-101: Safety and Pharmacodynamic Effects of ALKS 33-BUP Administered Alone and When Co-administered With Cocaine" atClinicalTrials.gov
^Correll CU, Newcomer JW, Silverman B, DiPetrillo L, Graham C, Jiang Y, et al. (December 2020). "Effects of Olanzapine Combined With Samidorphan on Weight Gain in Schizophrenia: A 24-Week Phase 3 Study".The American Journal of Psychiatry.177 (12):1168–1178.doi:10.1176/appi.ajp.2020.19121279.PMID32791894.S2CID221122225.
^Wentland MP, Lu Q, Lou R, Bu Y, Knapp BI, Bidlack, JM (April 2005). "Synthesis and opioid receptor binding properties of a highly potent 4-hydroxy analogue of naltrexone".Bioorganic & Medicinal Chemistry Letters.15 (8):2107–10.doi:10.1016/j.bmcl.2005.02.032.PMID15808478.
