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Ketamine for treatment-resistant depression: It’s fast and used once, it seems very low risk, appearing to specifically lower suicidal ideation. Are we ready for a paradigm shift toward faster agents like this, even if we know little about long-term outcomes?
Hi! Jim Phelps here for the Psychopharmacology Institute. A report from the Canadian Network for Mood and Anxiety Treatments (CANMAT) should help. The CANMAT has previously published detailed guidelines for the treatment of depression and bipolar disorders. Now, their 20-author review of the ketamine literature has been published in the Canadian Journal of Psychiatry. Let’s look at the CANMAT grading system so you know what their recommendations mean. They have 4 levels of evidence, which serves as a nice reminder for us of the hierarchy of evidence, from solid to shaky.
Level 1 means that a meta-analysis found multiple studies with very similar findings or there are at least 2 randomized trials with more than 30 patients in each treatment arm. Level 2 means there’s a meta-analysis, but the studies analyzed were heterogeneous—some positive and some negative—or there’s only 1 randomized trial, but it’s of decent size. Level 3 means there’s a small randomized trial—less than 30 patients in each arm or the study came from looking at health administration data. Finally, Level 4 means there were only anecdotal findings or expert opinion or an uncontrolled trial or a pilot randomized trial with 10 subjects or less in each arm.
On that scale, Levels 1 through 4, what do you think the CANMAT team found in the literature for the use of ketamine in treatment-resistant depression? You wouldn’t be surprised to learn that there is Level 1 evidence for a 1-time IV infusion of ketamine. The problem is, what’s the evidence for benefit from multiple infusions or ongoing maintenance? Well, it must be pretty good, right? Just look at all the ketamine treatment centers that have popped up in the United States. Oops! No. Evidence for benefit from repeated administrations of IV ketamine, according to this CANMAT review, is Level 3—no more than 1 small randomized trial.
Thus, the authors seem to be pointing away from ongoing or maintenance use of a series of IV administrations. For example, a recommendation is to start a previously untried antidepressant at the same time as a 1-time infusion even though this approach has not really been studied as such.
And what about intranasal esketamine? This form of ketamine has already received approval from Health Canada, the U.S. Food and Drug Administration, and the European Medicines Agency. The authors of this new review confined it to IV ketamine, but they did note that evidence so far suggests noninferiority of the intranasal form relative to the IV route. One more interesting detail and then we’ll conclude here with other recommendations from the authors: What about ketamine vs electroconvulsive therapy (ECT)?
Back when ketamine for depression was first being studied, I had some patients whom I thought might have been candidates, but there was nowhere to get it, let alone have it paid for by their insurance. So, I thought, “Hey, let’s request ECT but hold the electricity part; just use ketamine as the anesthetic and stop there.” Amazingly, I couldn’t convince insurance companies to pay for this, and only just now is ketamine vs ECT being studied in 2 head-to-head trials. These are due for completion in late 2022 and early 2023.
How about using ketamine as the anesthetic with ECT? Does ECT work faster? Several meta-analyses cited in this CANMAT review found that, yes, ECT responses are better early on with ketamine anesthesia, but adverse effects are more common than with standard anesthetic protocols.
To conclude, here are some further recommendations from the CANMAT authors. Relative contraindications include psychosis, substance use, pregnancy, a blood pressure above 140/90, or any unstable cardiovascular or respiratory conditions. The administering facility should have the ability to provide advanced cardiac life support, including necessary equipment and trained personnel, but an on-site anesthesiologist is not required. Antidepressants that are already underway can be continued, although increased caution is warranted with MAOIs regarding blood pressure. And lastly, because of shared GABA-ergic mechanisms, hold or taper off of a benzodiazepine before using ketamine.
For more, Box 1 in this paper is a must-read if you’re contemplating IV ketamine as a treatment option. It presents a whole page worth of detailed recommendations from the CANMAT authors. You can read more here.
Abstract
Objective: Patients with major depressive disorder often have limited response to first-line and second-line medications; hence, novel pharmacological treatments are needed for treatment-resistant depression (TRD). Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, has demonstrated rapid antidepressant effects in patients with TRD. The Canadian Network for Mood and Anxiety Treatments (CANMAT) convened a task force to review the evidence for efficacy and safety of racemic ketamine and to provide recommendations for its use in clinical practice.
Methods: A systematic review was conducted with computerized search of electronic databases up to January 31, 2020 using combinations of search terms, inspection of bibliographies, and review of other ketamine guidelines and consensus statements. The level of evidence and lines of treatment were assigned according to CANMAT criteria. Recommendations were given in question-answer format.
Results: Intravenous (IV) racemic ketamine given as a single infusion has Level 1 evidence for efficacy in adults with TRD. The evidence for multiple infusions, given as an acute series or as ongoing maintenance treatment, is limited to Level 3. Adverse events associated with ketamine infusions include behavioral (e.g., dissociative symptoms) and physiological (e.g., hypertension) events. There is only Level 3 or 4 evidence for non-IV formulations of racemic ketamine. Consensus recommendations are given for clinical administration of IV ketamine including patient selection, facility and personnel issues, monitoring, and maintaining response.
Conclusions: Single-dose IV racemic ketamine is a third-line recommendation for adults with TRD. The need for repeated and maintenance ketamine infusions should be carefully assessed on a case-by-case basis with consideration of potential risks and benefits. Because of limited evidence for efficacy and risk for misuse and diversion, the use of oral and other formulations of racemic ketamine should be limited to specialists with ketamine-prescribing expertise and affiliations with tertiary or specialized centers.
Keywords: antidepressants; depression; esketamine; glutamate; ketamine; major depressive disorder; treatment-resistant depression.
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Reference
Swainson, J., McGirr, A., Blier, P., Brietzke, E., Richard-Devantoy, S., Ravindran, N., … & Lam, R. W. (2021). The Canadian Network for Mood and Anxiety Treatments (CANMAT) task force recommendations for the use of racemic ketamine in adults with major depressive disorder: Recommandations du groupe de travail du réseau canadien pour les traitements de l’humeur et de l’anxiété (canmat) concernant l’utilisation de la kétamine racémique chez les adultes souffrant de trouble dépressif majeur. The Canadian Journal of Psychiatry, 66(2), 113-125.
