Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial

• Published in: The American journal of psychiatry Vol. 170; no. 10; pp. 1134 - 1142
• Main Authors: Murrough, James W., Iosifescu, Dan V., Chang, Lee C., Al Jurdi, Rayan K., Green, Charles E., Perez, Andrew M., Iqbal, Syed, Pillemer, Sarah, Foulkes, Alexandra, Shah, Asim, Charney, Dennis S., Mathew, Sanjay J.
• Format: Journal Article
• Language: English
• Published: Arlington, VA American Psychiatric Association 01-10-2013
• Subjects: Adult; Adult and adolescent clinical studies; Antidepressants; Antidepressive Agents - adverse effects; Antidepressive Agents - therapeutic use; Biological and medical sciences; Clinical outcomes; Clinical trials; Depression; Depressive Disorder, Major - diagnosis; Depressive Disorder, Major - drug therapy; Depressive Disorder, Major - psychology; Depressive Disorder, Treatment-Resistant - diagnosis; Depressive Disorder, Treatment-Resistant - drug therapy; Depressive Disorder, Treatment-Resistant - psychology; Double-Blind Method; Excitatory Amino Acid Antagonists - adverse effects; Excitatory Amino Acid Antagonists - therapeutic use; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Ketamine - adverse effects; Ketamine - therapeutic use; Male; Medical sciences; Mental depression; Middle Aged; Miscellaneous; Mood disorders; Neuropharmacology; Personality Inventory - statistics & numerical data; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychometrics; Psychopathology. Psychiatry; Psychopharmacology; Mood disorder; Treatment resistance; Ketamine; General anesthetic; Psychotropic; Antidepressant agent; Controlled therapeutic trial; Depression; Glutamate receptor; Drug of abuse; Antagonist; NMDA receptor
• ISSN: 0002-953X; 1535-7228
• DOI: 10.1176/appi.ajp.2013.13030392

Intravenous ketamine demonstrated rapid antidepressant effects in an optimized study design, improving depression severity in 64% of treatment-resistant patients 24 hours after a single dose. The double-blind trial provides evidence for the role of the N-methyl-d-aspartate glutamate receptor in depression, a receptor not currently activated by existing antidepressant drugs.
ObjectiveKetamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, has shown rapid antidepressant effects, but small study groups and inadequate control conditions in prior studies have precluded a definitive conclusion. The authors evaluated the rapid antidepressant efficacy of ketamine in a large group of patients with treatment-resistant major depression.MethodThis was a two-site, parallel-arm, randomized controlled trial of a single infusion of ketamine compared to an active placebo control condition, the anesthetic midazolam. Patients with treatment-resistant major depression experiencing a major depressive episode were randomly assigned under double-blind conditions to receive a single intravenous infusion of ketamine or midazolam in a 2:1 ratio (N=73). The primary outcome was change in depression severity 24 hours after drug administration, as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS).ResultsThe ketamine group had greater improvement in the MADRS score than the midazolam group 24 hours after treatment. After adjustment for baseline scores and site, the MADRS score was lower in the ketamine group than in the midazolam group by 7.95 points (95% confidence interval [CI], 3.20 to 12.71). The likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio, 2.18; 95% CI, 1.21 to 4.14), with response rates of 64% and 28%, respectively.ConclusionsKetamine demonstrated rapid antidepressant effects in an optimized study design, further supporting NMDA receptor modulation as a novel mechanism for accelerated improvement in severe and chronic forms of depression. More information on response durability and safety is required before implementation in clinical practice.