Question from a Member:
Do we have any information on antidepressants or medications that are best to use after ketamine infusions to maintain response?
On another page on this website, we discussed the off-label use of intravenous ketamine for major depressive disorder that has not improved sufficiently with standard treatments. But, if a patient with “treatment-resistant” major depressive disorder does respond to intravenous ketamine, what next?
An acute course of intravenous ketamine for major depressive disorder is typically considered to be six treatments—3 infusions per week for 2 weeks. The first thing to understand is that even if the depression improves significantly with intravenous ketamine, if we don’t do anything, there is a high chance that the patient will relapse back into the depression (Bobo et al., 2020).
What can we do to try to maintain the initial good response? After patients receive intravenous ketamine treatment by a facility that provides that treatment, they typically are referred back to us for continued treatment. That is why we have to know what the options are. There is very limited research evidence to answer our question but based on some published data and on clinical experience, there are options that we may consider to reduce the risk of relapse.
What gets them better, keeps them better?
If a patient with “treatment-resistant depression” responds to the initial 6 or so ketamine infusions, in clinical practice, intravenous ketamine infusions are often continued to reduce the risk of relapse even though the research data for this are limited.
Randomized clinical trials: None published for intravenous ketamine as of December 2020.
Open-label clinical trials: At least 3 small, open-label studies have reported that after a good response to an acute course of intravenous ketamine in major depressive disorder, continued infusions (once a week or once every two weeks) kept many patients well, at least in the short run—for 4 to 7 weeks (Phillips et al., 2019; Barenboim and Lafer, 2018; Vande Voort et al., 2016).
Published case series: Teams with experience and expertise have published case series in which many, though not all, patients with “treatment-resistant” major depressive disorder who responded to intravenous ketamine remained well for many months or even years with continued ketamine infusions without any serious side effects (Wilkinson et al., 2018; Archer et al., 2018).
Clinical experience: Clinicians who provide intravenous ketamine treatment report that, in their clinical experience, many patients stay well for many months with continued ketamine infusions. In my own patients with difficult-to-treat major depressive disorder who responded to an acute course of intravenous ketamine, the frequency of infusions was gradually reduced and this has been helpful in preventing relapse.
What should the frequency of infusions be?
How frequent the infusions need to be after a good response to the acute course is not clear but it is typically slowly decreased. For example, patients may receive the ketamine infusions once a week, then once every two weeks, and then, if possible, once a month. In clinical practice, many patients are reported to stay well even with one ketamine infusion per month.
Switch to esketamine nasal spray?
Given that esketamine nasal spray (Spravato®) is now available, some patients who respond to infusions of intravenous ketamine are then being started on esketamine nasal spray.
As of December 2020, I could not find any published clinical trial of switching to intranasal ketamine after a good response to intravenous ketamine. What we have is evidence suggesting that intranasal ketamine may continue to work beyond the short term.
– A randomized, double-blind controlled clinical trial found that patients with major depressive disorder who had responded well to the combination of a conventional oral antidepressant plus intranasal ketamine were less likely to relapse if they were continued on that combination than if they were switched to continuing the oral antidepressant but with a saline (placebo) nasal spray (Daly et al., 2019).
– Another clinical trial that did not have a control group found that patients with major depressive disorder who had a good response to intranasal ketamine plus an oral antidepressant tended to continue to be better when the combination was continued for up to one year (Wajs et al., 2020).
Go back to well-established treatments?
The CANMAT Task Force Recommendations for the Use of Racemic Ketamine in Adults with Major Depressive Disorder (Swainson et al., 2020) gave the opinion that: “Until there is higher quality evidence for relapse prevention, maintenance ketamine should be considered only when other evidence-based treatment options have been exhausted…”.
Yes, but, as of December 2020, we don’t have any evidence-based options for continuation or maintenance treatment in persons with “treatment-resistant” major depressive disorder whose depression improved only after intravenous ketamine was given. I guess they meant evidence-based treatment options that are used in patients whose depression is not “treatment-resistant”.
The guideline recommended that “Although there is no supporting evidence, it seems reasonable to start the patient on a previously untried antidepressant (or adjunctive agent) when initiating an acute course of ketamine infusions, or shortly after, in the hope that response can be maintained on the medication alone” (Swainson et al., 2020).
Sure, there’s obviously no harm in trying another antidepressant and/or augmenting agent that has not been tried before. But, in most cases, many well-established strategies have already been tried before the intravenous ketamine is tried.
So, the question really is—could some patients respond to standard antidepressant or augmentation strategies after getting better on intravenous ketamine even if the depression didn’t improve on similar treatments in the past? We don’t have a reliable answer to that.
But, there is a category of patients in whom this strategy of using standard treatments after a good response to intravenous ketamine could be more likely to work—those in whom intravenous ketamine was given for acute suicidality rather than due to a high level of treatment-resistance. Once the high level of suicidality has subsided, the treatment of major depressive disorder could be continued based on standard approaches because in many cases, the depression in this subcategory of patients may have not have failed to respond to a long list of standard treatments. To be clear, I am talking about patients in whom the reason for giving intravenous ketamine was not that the depression had not responded to most standard treatments but rather that there was a sharp increase in suicidal ideation. I have seen intravenous ketamine produce an amazing decrease in suicidality in some of my patients.
One simple but important thing to keep in mind is that we should think ahead and generally try to start the standard antidepressant or augmentation strategy early on—simultaneously with the course of intravenous ketamine. This is because standard treatments for major depressive disorder take some time to kick in.
There are some other options that could theoretically be considered for maintaining response to intravenous ketamine for “treatment-resistant” depression but that are currently either not recommended or not feasible in clinical practice. Still, let’s mention them briefly here since you may hear or read about them.
1. Ketamine by other routes?
Ketamine has also been used for “treatment-resistant” major depressive disorder by several routes other than intravenous:
– Oral (Nuñez et al., 2020; Rosenblat et al., 2019; Domany et al., 2019)
– Intranasal (Lee et al., 2019)
– Sublingual (Swainson and Khullar, 2020)
– Subcutaneous (George et al., 2017; Loo et al., 2016; Gálvez et al., 2014).
But, in my opinion, now that intranasal esketamine (Spravato®) is FDA-approved, it is less likely that these other routes for off-label use of ketamine for “treatment-resistant” depression will be widely used in clinical practice.
2. Other NMDA receptor antagonists?
Since ketamine is an antagonist of glutamatergic NMDA receptors, other medications acting on the glutamate system have been tried for maintaining response due to intravenous ketamine.
The clinical trials of riluzole (Ibrahim et al., 2012; Mathew et al., 2010) and of D-cycloserine (Chen et al., 2019) for major depressive disorder published as of December 2020 did not find them to be effective for this purpose. But, they haven’t been convincingly shown to not be effective either. Those interested in a little more detail on this can see the “Optional to read” notes below.
The problem of what to do to maintain a good response after an acute course of intravenous ketamine for “treatment-resistant” major depressive disorder is A major unmet need” (Papakostas, 2020). For now, one of the strategies discussed above will have to be chosen on a case-by-case basis. As more data are published that may guide our choices, we will update this article.
Optional to read:
Riluzole? Riluzole is a “glutamate modulator” whose exact pharmacodynamic effects are not fully clear. Two small controlled clinical trials did not find riluzole to be efficacious for maintaining response after intravenous ketamine (Ibrahim et al., 2012; Mathew et al., 2010). But, this could have been a type II error due to the small sample size. Also, we should note that both these studies involved the use of riluzole after just one infusion of ketamine.
D-cycloserine? In higher doses, D-cycloserine acts as a glutamate receptor antagonist. In a small but randomized and placebo-controlled clinical trial, it was not shown to be more effective than placebo for maintaining the improvement in depression (Chen et al., 2019). But, this could have been a type II error due to the small sample size. Also, we should note that both these studies involved the use of riluzole after just one infusion of ketamine. Finally, in posthoc analysis, D-cycloserine was associated with a greater reduction in suicidality than placebo.
I am deliberately not considering the study on lithium by Costi et al., 2019. If you want to know why that is, email me at email@example.com.]
Simple and Practical Medical Education thanks Nancy Diazgranados, MD, MS, for peer-reviewing and approving this article in December 2020.
Dr. Diazgranados is a psychiatrist in Bethesda. She was involved in many of the landmark research on intravenous ketamine done at the National Institutes of Health. To mention only two of them, these included the first published randomized clinical trial of intravenous ketamine in bipolar depression (Diazgranados et al., 2010) and the study cited above of riluzole after intravenous ketamine (Ibrahim et al., 2012).
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