A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression

Summary & key facts

Researchers tested whether a single dose of ketamine given into a vein could lift symptoms fast in people whose major depression had not improved with usual treatments. Eighteen people took part. Each person received ketamine on one test day and a placebo on another day, and neither they nor the raters knew which was given at the time. Depression scores improved within about two hours after ketamine and stayed better for about a week for many people. The study shows a fast and strong antidepressant effect after one infusion, but it was small and short-term, so we do not know how this would work long term or for everyone with depression.

Key facts:

• The study included 18 people with treatment-resistant major depression, meaning their depression had not gotten better with standard treatments.
• Each person received one intravenous infusion of ketamine at a dose of 0.5 mg per kg of body weight on one test day and a placebo on another test day, one week apart, after a two-week drug-free period.
• Neither the patients nor the people rating their symptoms knew which infusion was given, so the comparisons were blind.
• Depression scores were measured at several times up to one week after each infusion using a standard depression rating scale.
• Depression improved compared with placebo within about 110 minutes after the ketamine infusion, and the difference stayed statistically meaningful for the following week.
• About 71 out of 100 people who got ketamine met the study's definition of a response the day after treatment, and about 29 out of 100 were in remission the day after treatment.
• About 35 out of 100 people who got ketamine kept their response for at least one week.
• The size of the antidepressant effect was described as very large after 24 hours and still moderate to large after one week, but those descriptions come from statistical measurements rather than everyday measures of feeling better.
• The study tested a single dose and followed people for only one week, and it was done at one research site with a small number of participants. Those limits mean we cannot assume the same results would happen long-term or in all patients with depression.

Abstract

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.

Topics

Neurotransmitter Receptor Influence on Behavior Treatment of Major Depression Tryptophan and brain disorders

Categories

Health Sciences Medicine Pharmacology

Tags

Alternative medicine Anesthesia Antidepressant Confidence interval Crossover study Depression (economics) Economics Hippocampus Internal medicine Ketamine Ketamine hydrochloride Macroeconomics Medicine Mood Pathology Placebo Psychiatry Psychology Randomized controlled trial

Substances

Ketamine

Conditions & symptoms

Depression Lack of energy or motivation Poor sleep Sadness or low mood