A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.
BACKGROUND
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.


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


METHODS
Mood Disorders Research Unit at the National Institute of Mental Health. Patients Eighteen subjects with DSM-IV major depression (treatment resistant).


METHODS
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.
Zarate
Carlos A
CA
Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, Bethesda, MD 20892, USA. zaratec@mail.nih.gov
Singh
Jaskaran B
JB
Carlson
Paul J
PJ
Brutsche
Nancy E
NE
Ameli
Rezvan
R
Luckenbaugh
David A
DA
Charney
Dennis S
DS
Manji
Husseini K
HK
D000328:Adult; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D018592:Cross-Over Studies; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004351:Drug Resistance; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007649:Ketamine / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010919:Placebos; D011569:Psychiatric Status Rating Scales / Q000706:statistics & numerical data; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
D000928:Antidepressive Agents; D018691:Excitatory Amino Acid Antagonists; D010919:Placebos; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine