A small group of patients with treatment-resistant major depression achieved symptom relief within hours of receiving a single low-dose intravenous infusion of ketamine. The low-dose anesthetic apparently triumphed in these patients where other treatments—including oral antidepressants, which can take 8 weeks or longer to "kick in"—failed. Indeed, significant symptom relief began to emerge within roughly 2 hours (110 minutes) of drug administration. Of the 18 participants in the placebo-controlled crossover trial, 71% achieved some degree of symptom relief within a day of receiving active treatment. Of those responders, 29% became nearly symptom-free within a day and met criteria for remission. Benefits lasted a week in 35% of participants.
The investigative team, from the National Institute of Mental Health (NIMH) and the Department of Health and Human Services in Bethesda, Maryland, were motivated by experimental findings that the glutamatergic system mediates depression pathogenesis and that interruption of N-methyl-d-aspartate (NMDA) receptors may alleviate symptoms of depression. The team set about exploring whether low-dose ketamine, an NMDA antagonist, would be therapeutic in humans. After a 2-week wash-out period, study participants received either placebo or a single infusion of ketamine at a dose of 0.5 mg/kg. With the exception of those who maintained a beneficial effect from the study drug, participants crossed over to the alternate treatment—either placebo or ketamine—the following week in accordance with the study protocol. Patients were evaluated at baseline and at 40, 80, 110, and 230 minutes postinfusion and 1, 2, 3, and 7 days after treatment.
Although the researchers stressed the unlikelihood that ketamine will be widely used for the treatment of major depression given its adverse-effect profile, their study findings provide great insight into the direction that drug development for antidepressant therapy could take: targeting NMDA receptors. The results of the study, which was conducted at the NIMH, appear in the August issue of Archives of General Psychiatry. The citation is Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856-864.