Text version
Now, let’s look at esketamine. This is the “S” enantiomer of ketamine, so there’s going to be a lot of interest in this as an adjunct for the treatment of depression. Indeed, it received in March 2019 an FDA indication for treatment-resistant depression in conjunction with an oral antidepressant in adults. They have defined treatment resistance as when a person has taken at least 2 different antidepressants of adequate dose and duration which were not effective or sufficiently effective. There have been 5 phase 3 studies, according to a 2018 Janssen press release, in treatment-resistant depression: 3 short-term studies and a withdrawal-style maintenance of effect study, meaning half the people went off of it and half stayed on with the placebo as the control; and then 1 long-term safety study. As far as I can tell, only 1 has been published. Let’s look at that trial.
First, a reminder on how this medication is administered. Because of the risk of adverse outcomes, including sedation and dissociation, as well as the abuse and misuse potential that we already understand from long-term street use of ketamine, this medication is only available through a restricted distribution system under what’s called a risk evaluation and mitigation strategy. When patients use it, they can’t drive or use heavy machinery for the rest of the day, rather like ECT. The spray can’t be taken home. All of that seems warranted in that, in the prescribing information, we can see that 40% of people on esketamine experienced dissociation, and 20% or 30% experienced nausea, dizziness, or vertigo.
What about the efficacy results in this trial? Well, almost all the authors worked for Janssen, so you have to take this with a pretty big grain of salt. You’ll see in a minute why I think that’s important. But like ketamine, we see an acute 20-point drop in the MADRS score, the Montgomery-Asberg Depression Rating Scale. The dosing continued every 3 or 4 days through 25 days. That’s when things get interesting, because at 2 weeks and thereafter, there is no difference from the placebo group. There is a big difference at Day 2, which is emphasized in the publication, where they had separate graphs showing that separation. But then the placebo group continued to improve gradually, reaching the same point that the esketamine group reached relatively right away.
How can we explain this placebo improvement? Well, first of all, the antidepressants that were conjoined with this esketamine could have been initiated on the very first day of the trial in the design of this study. The authors note that antidepressants were “initiated or optimized for all participants on Day 1.” Many of them were hospitalized at the beginning of this study. The improvement could be from the initiation of the antidepressant where, at 2 weeks, you would think that something would be happening if we believe that antidepressants actually work. Also, it could be from a regression to the mean since these were hospitalized patients at the outset. The placebo was saline, so it wasn’t an active comparator, like midazolam, that’s been used in some other randomized trials of ketamine. I think it’s unlikely that participants were figuring out or increasingly thinking that they were on esketamine. For example, their dissociation was minimal on placebo and reached near 0 after 2 weeks. So, it wasn’t that they were increasingly thinking they were on drugs. Something else was going on to account for this substantial placebo response.
Interestingly, there is a follow-up on Day 81, and that result isn’t shown in the outcome graphs but buried in Table 2. We find that by Day 81, the Beck depression score had dropped 18 points on placebo and 20 points on esketamine. The p-value there is 0.8. Likewise, remission at Day 81, called 3 months out, was 50% for placebo. It was 60% for esketamine. So, you can see why Janssen is really playing down these results. I think that’s just an overt manifestation. We don’t even see those results in the graph, only the better outcomes with an emphasis on the good results. I almost missed this until I really dug through the paper. So, 60% remission is very good. But observing the 50% remission on placebo, it looks like they studied a population with a very high probability of remission from the get-go. Finally, just to underline that a bit further, statistical separation from placebo was gone at 2 weeks, even while the dosing of the active drug was still underway. And yet, this drug gets an FDA indication using their fast track and breakthrough therapy designations.
I won’t offer any further editorial comment, just to note that, remember, ketamine and esketamine are NMDA receptor antagonists. As we have reviewed here at Psychopharmacology Institute in Volume 7, Quick Take 2, naltrexone, the opiate receptor antagonist, blocks this antidepressant response of these medications (at least ketamine). There is a suggestion here that the mechanism of action involves an opiate pathway, and that means we really need to look at the long-term effects of use of this medication, including how people do months after its discontinuation. The company has a 1-year trial. It’s not yet published (that I can find). In a press release, they said there were no significant adverse effects in a group that had switched from the esketamine to nasal placebo, meaning they should have had withdrawal if they were going to have anything bad happening to them. But, again, we’re relying on the company for what we know about these drugs so far.
In conclusion, I think this is a remarkably flimsy outcome compared to the excitement and the FDA indication that already attends this esketamine medication. If this is the best it can do, then given the complexity and the surely exorbitant expense, we should wait for a better reason to start using it. Perhaps there’s a role for acute treatment to address suicidal ideation, which it did diminish here, as it has done in the ketamine trials. But for more than a one-shot treatment, I’m utterly unconvinced that there is any value here at all on the data that we have seen so far.
Abstract
Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study
Carla M Canuso, Jaskaran B Singh, Maggie Fedgchin, Larry Alphs, Rosanne Lane, Pilar Lim, Christine Pinter, David Hough, Gerard Sanacora, Husseini Manji, Wayne C Drevets
Objective: The authors compared the efficacy of standard-of-care treatment plus intranasal esketamine or placebo for rapid reduction of symptoms of major depression, including suicidality, among individuals at imminent suicide risk.
Method: In a double-blind, multicenter, proof-of-concept study, 68 participants were randomly assigned to receive esketamine (84 mg) or placebo twice weekly for 4 weeks, in addition to comprehensive standard-of-care treatment. The primary efficacy endpoint was change in score from baseline to 4 hours after initial dose on the Montgomery-Åsberg Depression Rating Scale (MADRS). Clinician global judgment of suicide risk (from the Suicide Ideation and Behavior Assessment Tool) was also assessed. Secondary endpoints included these measures at 24 hours and double-blind endpoint at day 25.
Results: A significantly greater improvement in MADRS score was observed in the esketamine group compared with the placebo group at 4 hours (least-square mean difference=-5.3, SE=2.10; effect size=0.61) and at ∼24 hours (least-square mean difference=-7.2, SE=2.85; effect size=0.65), but not at day 25 (least-square mean difference=-4.5, SE=3.14; effect size=0.35). Significantly greater improvement was also observed in the esketamine group on the MADRS suicidal thoughts item score at 4 hours (effect size=0.67), but not at 24 hours (effect size=0.35) or at day 25 (effect size=0.29). Between-group reductions in clinician global judgment of suicide risk scores were not statistically different at any time point. The most common adverse events among participants in the esketamine group were nausea, dizziness, dissociation, unpleasant taste, and headache.
Conclusions: These preliminary findings indicate that intranasal esketamine compared with placebo, given in addition to comprehensive standard-of-care treatment, may result in significantly rapid improvement in depressive symptoms, including some measures of suicidal ideation, among depressed patients at imminent risk for suicide.
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Reference
Canuso, C. M., Singh, J. B., Fedgchin, M., Alphs, L., Lane, R., Lim, P., Pinter, C., Hough, D., Sanacora, G., Manji, H., & Drevets, W. C. (2018). Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: Results of a double-blind, randomized, placebo-controlled study. American Journal of Psychiatry, 175(7), 620-630
