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

Autor:	Richards EM; 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., Mathews DC; 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., Luckenbaugh DA; 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., Ionescu DF; 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., Machado-Vieira R; 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., Niciu MJ; 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., Duncan WC; 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., Nolan NM; 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., Franco-Chaves JA; 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., Hudzik T; AstraZeneca Neuroscience Innovative Medicines, Cambridge, MA, USA.; AbbVie, Chicago, IL, USA., Maciag C; AstraZeneca Neuroscience Innovative Medicines, Cambridge, MA, USA.; Sage Therapeutics, Cambridge, MA, USA., Li S; AstraZeneca Neuroscience Innovative Medicines, Cambridge, MA, USA., Cross A; AstraZeneca Neuroscience Innovative Medicines, Cambridge, MA, USA., Smith MA; AstraZeneca Neuroscience Innovative Medicines, Cambridge, MA, USA., Zarate CA 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.
Jazyk:	angličtina
Zdroj:	Psychopharmacology [Psychopharmacology (Berl)] 2016 Mar; Vol. 233 (6), pp. 1119-30. Date of Electronic Publication: 2016 Jan 04.
DOI:	10.1007/s00213-015-4195-4
Abstrakt:	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. Competing Interests: The authors declare that they have no competing interests.
Databáze:	MEDLINE
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