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

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.

Fig. 1

Consort diagram for overall study design and total number of subjects screened

Fig. 2

Preclinical behavioral analysis of prenatally stressed (PNS) rats treated with AZD2327. a PNS rats treated with AZD2327 demonstrated increased latency to immobility at 1 and 3 mg/kg doses. This increase was similar to that seen when PNS rats were treated with imipramine (15 mg/kg). b PNS rats exhibited a phenotype consistent with anxiety as indicated by decreased time spent in the open arms of the elevated plus maze (EPM). This decrease was reversed when PNS rats were treated with AZD2327 (3 mg/kg) 30 min before testing t(49) = 6/120, p < 0.0001

Fig. 3

No significant differences were noted in several mood and anxiety rating scales over 4 weeks of treatment with AZD2327. a Hamilton Depression Rating Scale (HAM-D), b Hamilton Anxiety Rating Scale (HAM-A), and c HAM-D psychic anxiety item all showed no significant differences in treatment with active drug (6 mg/day) vs. placebo (N = 22)

Fig. 4

Log transformed AZ12311418 (major metabolite) levels by anxiety response over 4 weeks. Responders had significantly higher levels of AZ12311418 than nonresponders (F = 5.99, df = 1,11, p = 0.03, d = 1.49). No response by time interaction was observed (F = 1.42, df = 8,71, p = 0.20)

Fig. 5

Vascular endothelial growth factor (VEGF) levels were significantly lower across all time points in patients who received AZD2327. Compared to placebo (p = 0.02), no time by drug effect was observed