A Randomized Trial of a Low-Trapping Nonselective N-Methyl-D-Aspartate Channel Blocker in Major Depression

作者：Zarate Carlos A Jr^*; Mathews Daniel; Ibrahim Lobna; Chaves Jose Franco; Marquardt Craig; Ukoh Immaculata; Jolkovsky Libby; Brutsche Nancy E; Smith Mark A; Luckenbaugh David A

来源：Biological Psychiatry, 2013, 74(4): 257-264.

DOI：10.1016/j.biopsych.2012.10.019

• Antidepressant
• depression
• glutamate
• low-trapping NMDA
• rapid-acting
• treatment-resistant

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-Asberg 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-Asberg 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.

• 出版日期2013-8-15