Commentary on the Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Recommendations for the Use of Racemic Ketamine in Adults with Major Depressive Disorder

The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force recently provided recommendations for the use of racemic ketamine (R,S)-ketamine in adults with treatment-resistant depression (TRD).¹ Briefly, the guidelines noted Level 1 evidence for the efficacy of acutely administered intravenous (IV) (R,S)-ketamine in adults with TRD but suggested that this intervention be reserved as a third-line recommendation. In addition, the guidelines noted Level 3 evidence for using (R,S)-ketamine as continued or ongoing maintenance treatment and recommended that it be used on a case-by-case basis. Finally, the guidelines also noted Level 3 evidence for non-IV formulations of (R,S)-ketamine because the relatively few, and small, studies have received ratings of Level 3 or 4.

These guidelines are more than welcome. (R,S)-ketamine is a novel and mechanistically distinct treatment for TRD that is not approved by the U.S. Food and Drug administration (FDA). The guidelines seek, for the first time, to assess the usefulness of this agent based on clear evidence-based data and to place (R,S)-ketamine into treatment guidelines. To arrive at their recommendations, the members of the Task Force completed a comprehensive, computerized search of the literature. They further used a systematic and well validated approach to evaluate the level of evidence according to established CANMAT criteria. As a result, these guidelines provide a thorough, comprehensive, and highly usable guide for clinicians, allowing them to confidently evaluate the evidence and make the best possible treatment decisions for their patients.

One particularly important point of evidence in the CANMAT guidelines is that they state categorically and unequivocally that, “Ketamine, an NMDA receptor antagonist, has demonstrated rapid antidepressant effects in patients with TRD.” This statement has critical implications for public health more broadly and psychiatry in particular. Very few treatments are approved for TRD, and the guidelines underscore that (R,S)-ketamine is a rapid-acting pharmacological intervention for this indication. Furthermore, because very little information exists to guide clinicians after patients have failed to respond to first- or second-line medications, the strong evidence for the usefulness of (R,S)-ketamine is certainly welcome. Of particular usefulness to clinicians, the guidelines do an excellent job of summarizing several key criteria, including (1) recommendations and the corresponding levels of evidence regarding efficacy; (2) issues surrounding patient selection; (3) factors to consider for (R,S)-ketamine treatment; (4) treatment settings, personnel, and administration; and (5) monitoring (R,S)-ketamine infusions.

In short, the guidelines do an excellent job of placing what we know about (R,S)-ketamine into clinical context. Broadly, we know that (R,S)-ketamine is a rapid-acting antidepressant that produces therapeutic effects within hours, which distinguishes it from existing pharmacological approaches that take weeks or longer to exert antidepressant effects. We also know that its effects are quite robust within this very short time frame, particularly for patients who have failed to respond to multiple prior treatments and sometimes even electroconvulsive therapy (ECT), as well as patients with a history of multiple suicide attempts.^2,3 Some controlled data also suggest that (R,S)-ketamine may have therapeutic benefits in other disorders and symptom domains—including bipolar depression, post-traumatic stress disorder (PTSD), obsessive–compulsive disorder, social anxiety disorder, substance dependence, and suicidal ideation—although this evidence is preliminary and needs to be replicated in larger controlled studies.³ Nevertheless, (R,S)-ketamine’s efficacy in other symptom domains marks it as qualitatively distinct from most conventional antidepressants. In general, TRD patients are more likely than not to have these comorbid conditions and/or syndromes—indeed, managing comorbidity is often key to managing TRD—underscoring another potential advantage for (R,S)-ketamine use in this population. Unfortunately, because the data concerning (R,S)-ketamine use in these comorbid conditions are so preliminary, they could not be factored into the levels of evidence delineated in the present CANMAT guidelines.

Another reason why the CANMAT guidelines are particularly useful is that they offer a clear picture of both (R,S)-ketamine’s unique advantages and the other properties that preclude it from moving up in the rankings for maintenance treatment. Foremost among these is (R,S)-ketamine’s side effect profile, particularly its association with psychotomimetic effects and dissociation, as well as its abuse potential.⁴ These risks mean that (R,S)-ketamine is less likely to be compared to other existing treatments in head-to-head studies, which is necessary in order to establish its position in any treatment guidelines. Fortunately, some studies will soon compare (R,S)-ketamine to ECT in order to assess how they should be ranked with respect to one another in treatment guidelines.⁵ Also, because (R,S)-ketamine is currently used off-label, there is less incentive and funding available to support conducting large, controlled continuation and maintenance studies needed to provide evidence that would alter the level of evidence stated in the CANMAT guidelines. This begs the question of whether IV (R,S)-ketamine is currently stuck at Level 3 for continued or ongoing maintenance treatment. At present, my sense is that the answer to this question is yes. It is unlikely that a large, well-controlled, and adequately powered study will be conducted anytime soon to examine the maintenance efficacy of IV (R,S)-ketamine. As the Task Force members suggest, the closest maintenance option for now may be esketamine (the S-enantiomer of ketamine), which has FDA approval as an adjunctive treatment for TRD and for adults with major depression with acute suicidal ideation or behaviour. Interestingly, while esketamine is a viable choice, clinicians are presently more familiar with (R,S)-ketamine and have more experience with its use. In this context, the CANMAT guidelines are particularly important because they help clinicians appropriately assess (R,S)-ketamine relative to other treatments for TRD, including esketamine.

The authors acknowledge that these treatment guidelines may change in light of relevant, rapidly emerging data. It should be noted that, despite the comprehensive review and recommendations provided by these guidelines, many questions remain unanswered. For instance, a key question surrounds risk of relapse, which is particularly high after stopping a single (R,S)-ketamine administration (which the CANMAT guidelines currently place at Level 1). Given that the guidelines suggest that (R,S)-ketamine is at a Level 3 for maintenance treatment, what should clinicians do for patients who have responded very well to (R,S)-ketamine but not very well to conventional antidepressants? Should they continue prescribing conventional antidepressants without ongoing (R,S)-ketamine? Should they use esketamine for maintenance treatment even though few data exist to guide such a switch from (R,S)-ketamine to esketamine? Could patients who have responded to (R,S)-ketamine who are at high risk of suicide continue to receive IV (R,S)-ketamine? Despite the thoroughness of the Task Force’s efforts, guidelines such as these can offer only so much information, and many decisions will likely need to be made on a case-by-case basis. Until then, clinicians and patients are in desperate need of more information. In this context, the current CANMAT guidelines are a particularly valuable contribution that will help guide the use of (R,S)-ketamine.

In summary, the CANMAT guidelines for IV (R,S)-ketamine are a particularly important and much-needed step forward in the management of TRD. The guidelines provide a critical framework for why, when, how, and where to administer (R,S)-ketamine, though of course this could change as new data emerge regarding efficacy, drug formulation, side effects, or abuse potential. However, as the CANMAT guidelines make clear, (R,S)-ketamine is a valuable addition to the current armamentarium for mood disorders. Furthermore, studying the mechanistic processes and biomarkers that underlie its unique properties has significantly advanced drug development in this area.^6,7 (R,S)-ketamine provides hope that the field can continue to develop novel therapies similar to (R,S)-ketamine but without its limitations, and that these improved, next-generation treatments will soon serve as first-line therapies. Continued efforts to standardize guidelines on (R,S)-ketamine’s use across treatment sites is key and, because it might be increasingly challenging to conduct large, controlled studies, strong consideration should be given to the use of data registries.