A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression
Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al.;
Commented by , 24 Aug 2006
Background
The major proportion of antidepressants on the market are believed to exert their antidepressant function by increasing the intrasynaptic levels of monoamines. Unfortunately, these drugs take weeks to achieve their full effects. The major systems that have been postulated to mediate the delayed adaptive effects of antidepressants are neurotrophic signalling cascades and the glutaminergic system.
Ketamine, a well-known anasteticum, is believed to affect the glutaminergic system and further, preliminary data suggest that a single dose of ketamine may induce a rapid antidepressant effect in animals and humans. The present study investigates in a randomised controlled trial whether ketamine induces rapid and sustained response in patients with treatment refractory depression.
Method
18 subjects with major depression and who had not responded to two adequate antidepressant trials were randomized to intravenous ketamine (0.5 mg/kg) or saline in a double-blind crossover design. Subjects were rated 60 minutes prior to infusion and at 40, 80, 110, and 230 minutes, as well as 1, 2, 3, and 7 days after the infusion. The Hamilton Depression Rating Scale (HDRS) and the Beck Depression Inventory (BDI) were used.
Clinical response was defined as a 50% or greater decrease in the HDRS score from baseline and remission was defined as an HDRS score of 7 or lower.
Results
Patients who received ketamine scored significantly lower on the HDRS than those who received placebo already after 110 minutes and remained with lower scores through 7 days. One day after infusion, 12 (71%) out of 17 patients treated with ketamine met response criteria as compared with 0 of 14 patients treated with placebo. Five (29%) of 17 patients treated with ketamine met remission criteria 1 day after infusion compared with 0 patients who received placebo.
Patients treated with ketamine experienced euphoria but only for the first 110 minutes at most following infusion. None developed hypomania or mania.
Professor Kessing's comments
As the authors point out, no other treatment for depression is known that results in such a dramatic rapid and prolonged response with a single administration. It is remarkably that the effect of ketamine was prolonged for about one week, as the half-life for ketamine is about 2 hours. Thus, although ketamine is relatively selective for NMDA receptors that may be involved in the glutaminergic system, the possibility that the effect of ketamine is mediated in other ways cannot be excluded.
Shortcomings of the study are the little sample size and the possibility that blinding of the patients were not preserved due to the experience of short-lived perceptual disturbances related to ketamine. The findings cannot be generalised to patients with depression in general as the patients in the study suffered from treatment refractory depression.
The study raises a lot of intriguing questions - first of all:
-
can these results be replicated by other groups?
-
what happens with repeated infusions of ketamine, e.g. every week or so?
-
further, is intravenous treatment necessary?
It is encouraging that the National Institute of Mental Health supports such innovative and fascinating research.