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A randomized, placebo-controlled pilot trial of the delta opioid receptor agonist AZD2327 in anxious depression.

ABSTRACT: RATIONALE:Patients with anxious major depressive disorder (AMDD) have more severe symptoms and poorer treatment response than patients with non-AMDD. Increasing evidence implicates the endogenous opioid system in the pathophysiology of depression. AZD2327 is a selective delta opioid receptor (DOR) agonist with anxiolytic and antidepressant activity in animal models. OBJECTIVE:This double-blind, parallel group design, placebo-controlled pilot study evaluated the safety and efficacy of AZD2327 in a preclinical model and in patients with AMDD. METHODS:We initially tested the effects of AZD2327 in an animal model of AMDD. Subsequently, 22 subjects with AMDD were randomized to receive AZD2327 (3 mg BID) or placebo for 4 weeks. Primary outcome measures included the Hamilton Depression Rating Scale (HAM-D) and the Hamilton Anxiety Rating Scale (HAM-A). We also evaluated neurobiological markers implicated in mood and anxiety disorders, including vascular endothelial growth factor (VEGF) and electroencephalogram (EEG). RESULTS:Seven (54 %) patients responded to active drug and three (33 %) responded to placebo. No significant main drug effect was found on either the HAM-D (p?=?0.39) or the HAM-A (p?=?0.15), but the HAM-A had a larger effect size. Levels of AZ12311418, a major metabolite of AZD2327, were higher in patients with an anti-anxiety response to treatment compared to nonresponders (p?=?0.03). AZD2327 treatment decreased VEGF levels (p?=?0.02). There was a trend (p?

SUBMITTER: Richards EM

PROVIDER: S-EPMC5103283 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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A randomized, placebo-controlled pilot trial of the delta opioid receptor agonist AZD2327 in anxious depression.

Richards Erica M EM Mathews Daniel C DC Luckenbaugh David A DA Ionescu Dawn F DF Machado-Vieira Rodrigo R Niciu Mark J MJ Duncan Wallace C WC Nolan Neal M NM Franco-Chaves Jose A JA Hudzik Thomas T Maciag Carla C Li Shuang S Cross Alan A Smith Mark A MA Zarate Carlos A CA

Psychopharmacology 20160104 6

<h4>Rationale</h4>Patients with anxious major depressive disorder (AMDD) have more severe symptoms and poorer treatment response than patients with non-AMDD. Increasing evidence implicates the endogenous opioid system in the pathophysiology of depression. AZD2327 is a selective delta opioid receptor (DOR) agonist with anxiolytic and antidepressant activity in animal models.<h4>Objective</h4>This double-blind, parallel group design, placebo-controlled pilot study evaluated the safety and efficacy ...[more]

PMID: 26728893

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Project description:ObjectiveThe aim of this study was to determine if the non-convulsant delta-opioid receptor (DOR) agonist, KNT-127, could inhibit migraine-associated endpoints.BackgroundThe DOR has been identified as a therapeutic target for migraine. However, the development of delta agonists is limited as some ligands have seizurogenic properties, which may be related to their ability to induce receptor internalization. While both pro- and non-convulsant delta agonists can reduce migraine-associated allodynia, only the proconvulsant agonist, SNC80, has been shown to decrease cortical spreading depression (CSD). It is unclear if the ability of delta agonists to modulate cortical activity is related to the same signaling mechanisms that produce proconvulsant effects.MethodsThe effects of the non-convulsant delta agonist, KNT-127, were examined. Repetitive CSD was induced in female C57BL6/J (n = 6/group) mice by continuous application of KCl and the effect of KNT-127/vehicle (Veh) on both local field potentials and optical intrinsic signals was determined. To assess the effect of KNT-127 on established chronic migraine-associated pain, male and female C57BL6/J mice were treated with nitroglycerin (NTG; 10 mg/kg, ip) every other day for 9 days and tested with KNT-127 (5 mg/kg, sc) or Veh on day 10 (n = 6/group). DOR-enhanced green fluorescent protein mice (n = 4/group) were used to confirm the internalization properties of KNT-127 in the trigeminal ganglia, trigeminal nucleus caudalis, and somatosensory cortex.ResultsKNT-127 inhibited CSD events (t(10) = 3.570, p = 0.0051). In addition, this delta agonist also reversed established cephalic allodynia in the NTG model of chronic migraine (F(1, 20) = 12.80, p < 0.01). Furthermore, KNT-127 caused limited internalization of DOR in key migraine processing regions.ConclusionsThis study shows that the antimigraine effects of DOR agonists can be separated from their proconvulsant effects. This data provides valuable information for the continued development of delta agonists for the treatment of migraine.

Dataset Information

A randomized, placebo-controlled pilot trial of the delta opioid receptor agonist AZD2327 in anxious depression.

Publications

A randomized, placebo-controlled pilot trial of the delta opioid receptor agonist AZD2327 in anxious depression.

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