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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.

SUBMITTER: Li W

PROVIDER: S-EPMC4871611 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Major Depressive Disorder and Kappa Opioid Receptor Antagonists.

Li Wei W Sun Huijiao H Chen Hao H Yang Xicheng X Xiao Li L Liu Renyu R Shao Liming L Qiu Zhuibai Z

Translational perioperative and pain medicine 20160101 2

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 em ...[more]

PMID: 27213169

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Project description:Background: Major Depressive Disorder (MDD) is a moderately heritable disorder with a high lifetime prevalence. At present, laboratory blood tests to support MDD diagnosis are not available. Methods: We used a classifier approach on blood gene expression profiles of a unique set of non-medicated subjects (MDD patients and controls) to select genes of which expression is predictive for disease status. To reveal blood gene expression changes related to MDD disease, we applied a powerful ex vivo stimulus to the blood, i.e. incubation with lipopolysaccharide (LPS; 10 ng/ml blood). Results: Based on LPS-stimulated blood gene expression using whole-genome microarrays in 42 subjects (primary cohort; 21 MDD patients (mean age 42.3 years), 21 healthy controls (mean age 41.9 years)), we identified a set of genes (CAPRIN1, CLEC4A, KRT23, MLC1, PLSCR1, PROK2, ZBTB16) that serves as a molecular signature of MDD. These findings were validated for the primary cohort using an independent quantitative PCR method (P = 0.007). The difference between depressive patients and controls was confirmed (P = 0.019) in a replication cohort of 13 patients with MDD (mean age 42.8 years) and 14 controls (mean age 45.6 years). The MDD-signature score comprised of expression levels of 7 genes could discriminate depressive patients from controls with sensitivity of 76.9% and specificity of 71.8%. Conclusions: We show for the first time that molecular analysis of stimulated blood cells can be used as an endophenotype for MDD diagnosis, which is a milestone in establishing biomarkers for neuropsychiatric disorders with moderate heritability in general. Our results may provide a new entry point for following and predicting treatment outcome, as well as prediction of severity and recurrence of MDD. In total, 33 MDD patients and 34 healthy controls were analyzed using basal gene expression in whole blood, and gene expression from whole blood that was stimulated with LPS for 5-6 h, using microarrays. Patients were arbitrarily selected from all patients to serve as primary cohort (nMDD = 21 (MDD01-MDD21); nControls = 21 (Con01-Con21)), or replication cohort (nMDD = 12 (MDD22-MDD35); nControls = 13 (Con22-Con37)) using microarrays. This submission does not include Samples CON21_LPS or CON30_LPS.

Dataset Information

Major Depressive Disorder and Kappa Opioid Receptor Antagonists.

Publications

Major Depressive Disorder and Kappa Opioid Receptor Antagonists.

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