title: A randomized, placebo-controlled pilot trial of the delta opioid receptor agonist AZD2327 in anxious depression.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  These results suggest that AZD2327 has larger potential anxiolytic than antidepressant efficacy. Additional research with DOR agonists should be considered.
authors.affiliation: 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.
authors.forename: Erica M
authors.initials: EM
authors.lastname: Richards
authors.affiliation: 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.|Lundbeck LLC, Chicago, IL, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Mathews
authors.affiliation: 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.
authors.forename: David A
authors.initials: DA
authors.lastname: Luckenbaugh
authors.affiliation: 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.|Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Dawn F
authors.initials: DF
authors.lastname: Ionescu
authors.affiliation: 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.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Machado-Vieira
authors.affiliation: 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.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Niciu
authors.affiliation: 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.
authors.forename: Wallace C
authors.initials: WC
authors.lastname: Duncan
authors.affiliation: 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.
authors.forename: Neal M
authors.initials: NM
authors.lastname: Nolan
authors.affiliation: 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.|Veteran Affairs Caribbean Healthcare System, San Juan, Puerto Rico.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Franco-Chaves
authors.affiliation: AstraZeneca Neuroscience Innovative Medicines, Cambridge, MA, USA.|AbbVie, Chicago, IL, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hudzik
authors.affiliation: AstraZeneca Neuroscience Innovative Medicines, Cambridge, MA, USA.|Sage Therapeutics, Cambridge, MA, USA.
authors.forename: Carla
authors.initials: C
authors.lastname: Maciag
authors.affiliation: AstraZeneca Neuroscience Innovative Medicines, Cambridge, MA, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Li
authors.affiliation: AstraZeneca Neuroscience Innovative Medicines, Cambridge, MA, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Cross
authors.affiliation: AstraZeneca Neuroscience Innovative Medicines, Cambridge, MA, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.affiliation: 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.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Zarate
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D014151:Anti-Anxiety Agents / Q000627:therapeutic use*; D001007:Anxiety / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D001549:Benzamides / Q000627:therapeutic use*; D001921:Brain / Q000503:physiopathology; D003865:Major Depressive Disorder / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D004311:Double-Blind Method; D004569:Electroencephalography; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D010879:Piperazines / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D055815:Young Adult
chemical_list: C560622:4-((3-aminophenyl)(4-(4-fluorobenzyl)piperazin-1-yl)methyl)-N,N-diethylbenzamide; D014151:Anti-Anxiety Agents; D001549:Benzamides; D010879:Piperazines; D017465:Receptors, Opioid, delta; D042461:Vascular Endothelial Growth Factor A
keywords: AZD2327; Anxiety; Anxiolytic; Anxious depression; BDNF; Biomarkers; EEG; Major depressive disorder; Opiate; Preclinical