A randomized trial of a low-trapping nonselective N-methyl-D-aspartate channel blocker in major depression

Abstract

Background: The high-affinity N-methyl-D-aspartate (NMDA) antagonist ketamine exerts rapid antidepressant effects but has psychotomimetic properties. AZD6765 is a low-trapping NMDA channel blocker with low rates of associated psychotomimetic effects. This study investigated whether AZD6765 could produce rapid antidepressant effects in subjects with treatment-resistant major depressive disorder (MDD).

Methods: In this double-blind, randomized, crossover, placebo-controlled study, 22 subjects with DSM-IV treatment-resistant MDD received a single infusion of either AZD6765 (150 mg) or placebo on 2 test days 1 week apart. The primary outcome measure was the Montgomery-Åsberg Depression Rating Scale, which was used to rate overall depressive symptoms at baseline and 60, 80, 110, and 230 min postinfusion and on Days 1, 2, 3, and 7 postinfusion. Several secondary outcome measures were also used, including the Hamilton Depression Rating Scale.

Results: Within 80 min, Montgomery-Åsberg Depression Rating Scale scores significantly improved in subjects receiving AZD6765 compared with placebo; this improvement remained significant only through 110 min (d = .40). On the Hamilton Depression Rating Scale, a drug difference was found at 80 and 110 min and at Day 2 (d = .49). Overall, 32% of subjects responded to AZD6765, and 15% responded to placebo at some point during the trial. No difference was observed between the groups with regard to psychotomimetic or dissociative adverse effects.

Conclusions: In patients with treatment-resistant MDD, a single intravenous dose of the low-trapping NMDA channel blocker AZD6765 was associated with rapid but short-lived antidepressant effects; no psychotomimetic effects were observed.

Trial registration: ClinicalTrials.gov NCT00986479.

Keywords: Antidepressant; depression; glutamate; low-trapping NMDA; rapid-acting; treatment-resistant.

Figure 1

Change in Montgomery Asberg Depression Rating Scale (MADRS), Brief Psychiatric Rating Scale (BPRS) positive symptom, and Young Mania Rating Scale (YMRS) scores over one week (n=22). Values are expressed as generalized least square means and standard errors for the Intent to Treat (ITT) analysis. *indicates P<0.05, ** P <0.01, *** P <0.001.

Figure 2

(A) Proportion of responders (50% improvement on Montgomery Asberg Depression Rating Scale (MADRS)) to AZD6765 and placebo from 60 minutes to Day 7 post-infusion (n=22). (B) Proportion of remitters (MADRS <10) on AZD6765 and placebo from 60 minutes to Day 7 post-infusion (n=22).