Friday, August 18, 2006

Fast treatment of depression! Or, "I'm still in a hole, but now it's a different one." Oh, the irony.

Wanted to share this with you all, in case you haven't seen it yet:

From: Archives of General Psychiatry


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


Carlos A. Zarate, Jr, MD; Jaskaran B. Singh, MD; Paul J. Carlson, MD; Nancy E. Brutsche, MSN; Rezvan Ameli, PhD; David A. Luckenbaugh, MA; Dennis S. Charney, MD; Husseini K. Manji, MD, FRCPC

Arch Gen Psychiatry. 2006;63:856-864.

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.

Trial Registration clinicaltrials.gov Identifier: NCT00088699.


Author Affiliations: Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, Bethesda, Md.


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So, ketamine has all sorts of uses-- legal and illegal. It's a hallucinogenic street drug (vitamin K, special K, etc), a dissociative anesthetic, and a research tool. It's a noncompetitive NMDA antagonist and the experience is sometimes called "getting in the hole" or simply, "the K-hole," because it makes the users feel like they are far-removed from the real world and can't move in order to interact with it. Imagine looking up from the bottom of a very deep and narrow well...

The study inolved 18 TRD patients who they randomized in a double-blind crossover study (the other week was spent giving saline). The subjects, on average, were middle-aged women with about 6 (!) prior full antidepressant trials; some had ECT. So, these are sick folks. One person dropped out of the placebo arm due to a medical problem. Noone receiving ketamine had side effects that led them to drop out. The most amazing thing about the study is that everyone got better! The vast majority of patients/subjects (71%) responded. The rest remitted (!).

What I most liked about this study was that its design is very clear. The subjects were their own controls. I also liked, well, the fact that this whole study is really awesome. I mean, rapid improvement in TRD? Yes, it's possible. You have to agree that this is one of the most provocative studies to come out in a loooong time regarding well, most anything in psychiatry (Kapur's Fast Dissociation article is one of these, too).


What I didn't like was that though the authors say the study was a double-blind crossover study, they never actually state that the folks performing the outcome ratings were blinded! This could be a big problem. Furthermore, the recruitment of the patients leaves room for speculation. The two sources of patients were very different: inpatient psych units versus newspaper ads. Hmm. Folks responding to newspaper ads may be much less acute than those already on an inpatient service. I'd like to see how response/remission sorts according to where the patients came from. On the otherhand, everyone got better, so this really isn't a big deal. It may, in fact, argue for generalizability beyond what the authors allow.

Nonetheless, this is quite an article and I can't wait to see how it plays out in psychiatry circles, academic institutions, trade journals, Big Pharma, etc
.

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