Ketamine
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Ketamine Matches 'Gold Standard' in Major Depression Trial
When it came to improving treatment-resistant major depression in outpatients without psychotic features, ketamine worked just as well as electroconvulsive therapy (ECT), the ELEKT-D randomized trial found.
Following a 3-week treatment period, 55.4% of the patients in the ketamine group and 41.2% of those in the ECT group had a treatment response, a 14.2% difference (95% CI 3.9-24.2) that fell well within the trial's noninferiority threshold (P<0.001), reported Amit Anand, MD, of Brigham and Women's Hospital in Boston, and colleagues.
Response was defined as a 50% or greater drop from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16).
The results were presented at the American Psychiatric Associationopens in a new tab or window (APA) annual meeting and simultaneously published in the New England Journal of Medicineopens in a new tab or window.
"That ketamine was noninferior was in itself surprising, as ECT is the gold standard for 80 years for treatment of resistant depression," Anand told MedPage Today. "And actually, ketamine's effectiveness, in the aggregate results, looks a bit better than ECT for major depression not associated with psychotic features."
"However, our starting hypothesis and study design was to find whether ketamine was noninferior to ECT," Anand explained. "So in the paper, we cannot comment on ketamine's superiority compared to ECT for treatment of non-psychotic resistant depression."
In an accompanying editorialopens in a new tab or window, Robert Freedman, MD, of the University of Colorado School of Medicine in Aurora, pointed out that "[i]t is noteworthy that all the patients who were considered for trial entry were initially referred for ECT because they and their clinicians thought that ECT was their best option."
Similar findings were seen when looking at treatment response measured by at least a 50% decrease in Montgomery-Åsberg Depression Rating Scale (MADRS) score. This was achieved by 50.8% of ketamine-treated patients and 41.1% of ECT patient
"0.5 mg per kilogram of body weight over 40 minutes"
For the sake of comparison, to induce anesthesia in someone using ketamine, I'd give about 4 times (2mg/kg) that amount. That would induce unconsciousness and maintain hemodynamic stability. It would also be given over about 10 seconds, achieving very high blood levels.
If I had a "spotty" epidural, ketamine was my 2nd-line drug (after (gasp!) fentanyl). A quarter of a milligram per kilogram (again) as a bolus would cause some pretty good analgesia and also a bit of "weird-trip" like sensations. Again, this is as a bolus, not over 40 minutes.
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Ketamine is a weird, weird drug, and it's been around forever. I find it interesting (?) that people are trying to reinvent indications for its use.
In this study, if you give ketamine to depressed patients who are undergoing anesthesia for other things, there was no beneficial effect of ketamine. However, you have to wonder about what effect other medications given during the surgery might have had. Also, the ketamine given as a bolus, rather than an infusion over 40 minutes.
Still, interesting (at least to me).
Trial of Ketamine Masked by Surgical Anesthesia in Depressed Patients
BACKGROUND Ketamine may have antidepressant properties, but its acute psychoactive effects complicate successful masking in placebo-controlled trials.
METHODS In a triple-masked, randomized, placebo-controlled trial, 40 adult patients with major depressive disorder were randomized to a single infusion of ketamine (0.5 mg/kg) or placebo (saline) during anesthesia for routine surgery. The primary outcome was depression severity measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) at 1, 2, and 3 days post-infusion. The secondary outcome was the proportion of participants with clinical response (≥50% reduction in MADRS scores) at 1, 2, and 3 days post-infusion. After all follow-up visits, participants were asked to guess which intervention they received.
RESULTS Mean MADRS scores did not differ between groups at screening or pre-infusion baseline. The mixed-effects model showed no evidence of effect of group assignment on post-infusion MADRS scores at 1 to 3 days post-infusion (-5.82, 95% CI -13.3 to 1.64, p=0.13). Clinical response rates were similar between groups (60% versus 50% on day 1) and comparable to previous studies of ketamine in depressed populations. Secondary and exploratory outcomes found no evidence of benefit for ketamine. 36.8% of participants guessed their treatment assignment correctly; both groups allocated their guesses in similar proportions.
CONCLUSION A single dose of intravenous ketamine compared to placebo has no short-term effect on the severity of depression symptoms in adults with major depressive disorder. This trial successfully masked treatment allocation in moderate-to-severely depressed patients using surgical anesthesia. While it is impractical to use surgical anesthesia for most placebo-controlled trials, future studies of novel antidepressants with acute psychoactive effects should make efforts to fully mask treatment assignment in order to minimize subject-expectancy bias.
