Relative Efficacy Ketamine : Does the Formulation and Delivery Matter with Respect to Efficacy, Tolerability and Safety?
In March of 2019, the US FDA approved intranasal esketamine for treatment-resistant depression (TRD). Conceptually, this is an extraordinary event from the point of view of drug development in psychiatry insofar as this is the first time the FDA has approved an antidepressant medicine that was developed on the basis of an a priori diseases model (i.e. glutamatergic dysregulation relevant to the pathogenesis of mood disorders). Historically, antidepressants that are FDA approved, at least the earlier versions, were developed and discovered largely based on serendipity. From a pragmatic perspective, there are many unanswered questions beginning but not ending with who is the right patient and when should they receive intranasal esketamine, as part of the algorithmic approach to treatment selection. An additional question that is now posed is which formulation of ketamine is more effective, safe, and better tolerated?
The foregoing questions takes on considerably more relevance in light of the fact that in the past decade, there has been a large number of centers across the U.S. and a center recently opened in Canada that provide intravenous ketamine for individuals meeting criteria for TRD (variably defined). In light of the FDA approval for intranasal esketamine and its substantial development and establishment of safety and tolerability, should it be considered in all cases ahead of intravenous ketamine? Will existing “ketamine clinics” that offer intravenous ketamine offer both treatments as part of a “suite” of options? Which treatment is more cost-effective? Which treatment is better for long term recurrence prevention? Which treatment is better able at addressing patient reported outcomes (PROs) (e.g. quality of life, functioning, return to positive mental health?)? Are dissociative symptoms more severe, enduring and/or recurrent with one formulation versus the other? Are safety concerns (e.g. cardiovascular) different across the formulations? What are patient’s preferences and what are payers more inclined to reimburse?
The foregoing torrent of questions is not an exhaustive list but illustrates the important point of care questions we are now faced with. Hopefully, evidence and good scientific method is able to inform the appropriate decisions. No direct head-to-head comparison of intravenous ketamine versus intranasal esketamine has been conducted where in the overarching aims are to ascertain relative efficacy, acceptability, tolerability, safety and/or cost-effectiveness, such studies need to be done and presumably will be. There is precedent for believing that different formulations possess different therapeutic benefits. In light of recent study results indicating that although oral ketamine may offer some degree of benefit, its overall therapeutic effect does not appear to be as robust acutely and may not be as rapid onset in action when compared to IV formulations.
One way to address the relative efficacy of IV ketamine versus IN ketamine, in the absence of a head-to-head trial, is a network meta-analysis (NMAs) (otherwise referred to as indirect comparative effectiveness studies) which has become very popular in effectiveness research across medicine, including psychiatry. The impetus for NMAs is the need for comparative effectiveness in guiding treatment selection for many medical disorders. There will never be sufficient evidence and/or enough head-to-head comparison treatments that clinicians are asked to select from a day-to-day basis. Notwithstanding the significant contribution that NMAs can make with respect to providing some insights regarding comparative efficacy, the major limitations of NMAs is what is referred to as “transitivity assumption”. Loosely, transitivity assumption refers to the assumption that if intervention A is compared to intervention B, and intervention B is superior to intervention C, then intervention A must be better than intervention C because all other factors across the studies are for the most part common. This is an assumption that has many flaws, particularly in psychiatry where recapitulating many factors across studies is unlikely the case (as evidenced by rising placebo response rates).
Where does that leave us? At the current time, we don’t know which formulation offers a more beneficial therapeutic index and/or is more cost-effective in the short or long term. Moreover, we also don’t know which treatment is more rapid in its onset of action and/or is able to sustain benefits longer in a cost-effective way. Relative anti-suicide effects are unknown. A host of research groups are currently attempting to conduct studies attempting to answer these questions, and it is anticipated that answers to these questions will be known by the end of the year 2019.