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Psychopharmacology (Berl). 2016 Mar;233(6):1119-30. doi: 10.1007/s00213-015-4195-4. Epub 2016 Jan 4.

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

Author information

1
Experimental Therapeutics and Pathophysiology Branch, Department of Health and Human Services, National Institute of Mental Health, National Institutes of Health, 10 Center Drive CRC, Room 7-5545, Bethesda, MD, 20892, USA. erica.richards@nih.gov.
2
Experimental Therapeutics and Pathophysiology Branch, Department of Health and Human Services, National Institute of Mental Health, National Institutes of Health, 10 Center Drive CRC, Room 7-5545, Bethesda, MD, 20892, USA.
3
Lundbeck LLC, Chicago, IL, USA.
4
Massachusetts General Hospital, Boston, MA, USA.
5
Veteran Affairs Caribbean Healthcare System, San Juan, Puerto Rico.
6
AstraZeneca Neuroscience Innovative Medicines, Cambridge, MA, USA.
7
AbbVie, Chicago, IL, USA.
8
Sage Therapeutics, Cambridge, MA, USA.

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 < 0.06) for those with an anti-anxiety response to have higher EEG gamma power than nonresponders.

CONCLUSION:

These results suggest that AZD2327 has larger potential anxiolytic than antidepressant efficacy. Additional research with DOR agonists should be considered.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00759395.

KEYWORDS:

AZD2327; Anxiety; Anxiolytic; Anxious depression; BDNF; Biomarkers; EEG; Major depressive disorder; Opiate; Preclinical

PMID:
26728893
PMCID:
PMC5103283
DOI:
10.1007/s00213-015-4195-4
[Indexed for MEDLINE]
Free PMC Article

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