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

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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.

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Acknowledgments

Funding for this work was supported in part by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; NCT00759395, Protocol 08-M-0196), by a NARSAD Independent Investigator to Dr. Zarate, and by a Brain & Behavior Mood Disorders Research Award to Dr. Zarate. Dr. Zarate had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The authors thank the 7SE research unit and staff for their support, and Mercy Uwakwe for assistance in performing the clinical BDNF and VEGF ELISA assays. Ioline Henter (NIMH) provided invaluable editorial assistance.

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Author notes

  1. Daniel C. Mathews

    Present address: Lundbeck LLC, Chicago, IL, USA

  2. Dawn F. Ionescu

    Present address: Massachusetts General Hospital, Boston, MA, USA

  3. Jose A. Franco-Chaves

    Present address: Veteran Affairs Caribbean Healthcare System, San Juan, Puerto Rico

  4. Thomas Hudzik

    Present address: AbbVie, Chicago, IL, USA

  5. Carla Maciag

    Present address: Sage Therapeutics, Cambridge, MA, USA

Authors and Affiliations

  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 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 & Carlos A. Zarate Jr.

  2. AstraZeneca Neuroscience Innovative Medicines, Cambridge, MA, USA

    Thomas Hudzik, Carla Maciag, Shuang Li, Alan Cross & Mark A. Smith

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  1. Erica M. Richards
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Corresponding author

Correspondence to Erica M. Richards.

Ethics declarations

The study was approved by the Combined Neuroscience Institutional Review Board (IRB) at the NIH. All subjects provided written informed consent before entry into the study and were assigned a Clinical Research Advocate from the NIMH Human Subjects Protection Unit to monitor the consent process and research participation throughout the study.

Conflict of interest

The authors declare that they have no competing interests.

Funding

Funding for this work was supported in part by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; NCT00759395, protocol 08-M-0196), by a NARSAD Independent Investigator to Dr. Zarate, and by a Brain & Behavior Mood Disorders Research Award to Dr. Zarate. These funding sources had no further role in study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. A patent for the use of ketamine in depression has been awarded that lists Dr. Zarate among the inventors; he has assigned his rights on the patent to the US government, but will share a percentage of any royalties that may be received by the government. Carla Maciag and Drs. Mark Smith, Thomas Hudzik, and Alan Cross were full-time employees of AstraZeneca Neuroscience Innovative Medicines at the time the study was conducted. AstraZeneca Pharmaceuticals provided the study compound.

Additional information

ClinicalTrials.gov Identifier: NCT00759395, Protocol 08-M-0196

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Richards, E.M., Mathews, D.C., Luckenbaugh, D.A. et al. A randomized, placebo-controlled pilot trial of the delta opioid receptor agonist AZD2327 in anxious depression. Psychopharmacology 233, 1119–1130 (2016). https://doi.org/10.1007/s00213-015-4195-4

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