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

Erica M Richards; Daniel C Mathews; David A Luckenbaugh; Dawn F Ionescu; Rodrigo Machado-Vieira; Mark J Niciu; Wallace C Duncan; Neal M Nolan; Jose A Franco-Chaves; Thomas Hudzik; Carla Maciag; Shuang Li; Alan Cross; Mark A Smith; Carlos A Zarate Jr

doi:10.1007/s00213-015-4195-4

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

Journal article

Peer reviewed

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

Erica M Richards, Daniel C Mathews, David A Luckenbaugh, Dawn F Ionescu, Rodrigo Machado-Vieira, Mark J Niciu, Wallace C Duncan, Neal M Nolan, Jose A Franco-Chaves, Thomas Hudzik, …

Psychopharmacology (Berlin, Germany), Vol.233(6), pp.1119-1130

03/2016

DOI: 10.1007/s00213-015-4195-4

PMCID: PMC5103283

PMID: 26728893

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Abstract

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

Electroencephalography

Depressive Disorder, Major - blood

Humans

Middle Aged

Male

Anxiety - drug therapy

Young Adult

Benzamides - therapeutic use

Adult

Female

Anti-Anxiety Agents - therapeutic use

Depressive Disorder, Major - drug therapy

Disease Models, Animal

Depressive Disorder, Major - physiopathology

Double-Blind Method

Anxiety - blood

Brain - physiopathology

Receptors, Opioid, delta

Vascular Endothelial Growth Factor A - blood

Anxiety - physiopathology

Piperazines - therapeutic use

Rats, Sprague-Dawley

Pilot Projects

Animals

Adolescent

Aged

Details

Title: Subtitle: A randomized, placebo-controlled pilot trial of the delta opioid receptor agonist AZD2327 in anxious depression
Creators: Erica M Richards - 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
Daniel C Mathews - Lundbeck LLC, Chicago, IL, USA
David A Luckenbaugh - 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
Dawn F Ionescu - Massachusetts General Hospital, Boston, MA, USA
Rodrigo Machado-Vieira - 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
Mark J Niciu - 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
Wallace C Duncan - 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
Neal M Nolan - 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
Jose A Franco-Chaves - Veteran Affairs Caribbean Healthcare System, San Juan, Puerto Rico
Thomas Hudzik - AbbVie, Chicago, IL, USA
Carla Maciag - Sage Therapeutics, Cambridge, MA, USA
Shuang Li - AstraZeneca Neuroscience Innovative Medicines, Cambridge, MA, USA
Alan Cross - AstraZeneca Neuroscience Innovative Medicines, Cambridge, MA, USA
Mark A Smith - AstraZeneca Neuroscience Innovative Medicines, Cambridge, MA, USA
Carlos A Zarate Jr - 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
Resource Type: Journal article
Publication Details: Psychopharmacology (Berlin, Germany), Vol.233(6), pp.1119-1130
DOI: 10.1007/s00213-015-4195-4
PMID: 26728893
PMCID: PMC5103283
NLM abbreviation: Psychopharmacology (Berl)
ISSN: 0033-3158
eISSN: 1432-2072
Publisher: Germany
Grant note: ZIA MH002927-07 / Intramural NIH HHS Intramural NIH HHS
Language: English
Date published: 03/2016
Academic Unit: Psychiatry; Iowa Neuroscience Institute
Record Identifier: 9984004180802771

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