title: Major Depressive Disorder and Kappa Opioid Receptor Antagonists.
abstract: Major depressive disorder (MDD) is a common psychiatric disease worldwide. The clinical use of tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitor (SNRIs) for this condition have been widely accepted, but they were challenged by unacceptable side-effects, potential drug-drug interactions (DDIs) or slow onset/lack of efficacy. The endogenous opioid system is involved in stress and emotion regulatory processes and its role in MDD has been implicated. Although several KOR antagonists including JDTic and PF-04455242 were discontinued in early clinical trials, ALKS 5461 and CERC-501(LY-2456302) survived and entered into Phase-III and Phase-II trials, respectively. Considering the efficacy and safety of early off-label use of buprenorphine in the management of the treatment-resistant depression (TRD), it will be not surprising to predict the potential success of ALKS 5461 (a combination of buprenorphine and ALKS-33) in the near future. Moreover, CERC-501 will be expected to be available as monotherapy or adjuvant therapy with other first-line antidepressants in the treatment of TRD, if ongoing clinical trials continue to provide positive benefit-risk profiles. Emerging new researches might bring more drug candidates targeting the endogenous opioid system to clinical trials to address current challenges in MDD treatment in clinical practice.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University.
authors.forename: Huijiao
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University.
authors.forename: Xicheng
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University.
authors.forename: Li
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania.
authors.forename: Renyu
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University.
authors.forename: Liming
authors.initials: L
authors.lastname: Shao
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University.
authors.forename: Zhuibai
authors.initials: Z
authors.lastname: Qiu
keywords: Antagonists; Kappa opioid receptor; Major depressive disorder