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Carlos A. Zarate, Jr, MD; Jaskaran B. Singh, MD; Paul J. Carlson, MD; Nancy E. Brutsche, MSN; Rezvan Ameli, PhD; David A. Luckenbaugh, MA; Dennis S. Charney, MD; Husseini K. Manji, MD, FRCPC

Arch Gen Psychiatry. 2006;63:856-864.

Context  Existing therapies for major depression have a lag of onset of action of several weeks, resulting in considerable morbidity. Exploring pharmacological strategies that have rapid onset of antidepressant effects within a few days and that are sustained would have an enormous impact on patient care. Converging lines of evidence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders.

Objective  To determine whether a rapid antidepressant effect can be achieved with an antagonist at the N-methyl-D-aspartate receptor in subjects with major depression.

Design  A randomized, placebo-controlled, double-blind crossover study from November 2004 to September 2005.

Setting  Mood Disorders Research Unit at the National Institute of Mental Health.

Patients  Eighteen subjects with DSM-IV major depression (treatment resistant).

Interventions  After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion.

Main Outcome Measure  Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale.

Results  Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week.

Conclusions  Robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week.

Trial Registration  clinicaltrials.gov Identifier: NCT00088699.

Author Affiliations: Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, Bethesda, Md.

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