Incorporating Rapid-Acting Antidepressants Into Clinical Practice Effectively and Safely

Rapid-acting antidepressants (RAADs), a new class of medication therapies that target glutamate and GABA, are the latest option for treating major depressive disorder (MDD) and treatment-resistant depression (TRD). How can clinicians incorporate RAADs into their practice, and what should they be mindful about before doing so?

In this podcast, Psych Congress Steering Committee Member Rakesh Jain, MD, MPH, answers clinical questions about the application of RAADs for mental health care, including off-label use, minimizing addiction and diversion risks, and the need to treat depressive episodes as quickly as possible.

Saundra Jain, MA, PsyD, LPC, adjunct clinical affiliate, University of Texas at Austin School of Nursing, moderates the Q&A session.

For more information about Psych Congress Regionals, visit the meeting website.

Rakesh Jain, MD, MPH, attended medical school at the University of Calcutta in India. He then attended graduate school at the University of Texas School of Public Health in Houston, where he was awarded a “National Institute/Center for Disease Control Competitive Traineeship”. His research thesis focused on the impact of substance abuse. He graduated from the School of Public Health in 1987 with a Masters of Public Health (MPH) degree.

Dr Jain served a 3-year residency in Psychiatry at the Department of Psychiatry and Behavioral Sciences at the University of Texas Medical School at Houston. He followed that by obtaining further specialty training, by undergoing a 2-year fellowship in Child and Adolescent Psychiatry. In addition, Dr Jain completed a postdoctoral fellowship in Research Psychiatry at the University of Texas Mental Sciences Institute, in Houston. He was awarded the “National Research Service Award” for the support of this postdoctoral fellowship.

Read the Transcript:

Saundra Jain, MA, PsyD, LPC: Well, welcome back everyone. Rakesh, it's so nice to see you this morning. Lot of interest in the presentation. We've got some great questions. So I say, let's jump in. I want to share our most popular question this morning. Here we go. As ketamine is only indicated for MDD, but have you used it in bipolar patients, and if so, what do you think? Was it effective?

Rakesh Jain, MD, MPH: Yes, you are completely right, dear colleague, that the formal indication for esketamine, Spravato, is for TRD, treatment resistant depression. But the truth is, it's actually indicated for treatment resistant major depression, because a depressive episode can come from bipolar disorder as well, as we all know. So it's not indicated. Having said that, it has been utilized, and the results have been as positive as they have been for unipolar depression, but it is off-label. So accessing it is a bit more challenging, but the data, while missing from clinical trials, from clinical experience, has been generally quite positive.

Dr. S Jain: That's good to know and I'm glad that you pointed out Rakesh, that it is off label. All right, another question, this one about ketamine. Clinicians are saying, I understand that ketamine also has activity in the opioid system. Can you talk about your thoughts about this as a role in mechanism as well as potential for abuse?

Dr. R Jain: Very thoughtful set of questions. It is accurate: ketamine is an NMDA receptor antagonist, but the downstream effects of that really do appear to be partly, but only partly, and indirectly on the opioid system, perhaps most likely on the mu receptor system. Therefore, blocking the mu system could actually decrease the effectiveness of ketamine, that's a possibility. Though in real life, Sandra, very often patients are on all kinds of mu receptor antagonists or agonists and they tend to respond fairly well to ketamine. So this worry may be more on paper, maybe partly in reality, but not entirely.

But the second part of the excellent question had to do with addiction potential or abuse potential. Without a doubt, ketamine does have that. It is on the low end. I recently saw a paper that evaluated the addiction risk of ketamine, and it placed it just under coffee. Now, coffee is fairly addicting. I can actually demonstrate that by showing you my cup and maybe you can do the same, Sandra, but if the addiction potential isn't wildly out there, it's something to keep our eyes on.

And that's, perhaps, one of the reasons why esketamine is so interesting, because it's only available through the REMS program. And the REMS program is specifically designed to protect the patient's health, but also to protect the potential for society having to deal with abuse and diversion issues. So all my colleagues out there who are using ketamine, intramuscularly, sublingually, or however, do keep your eyes fairly closely on the risk of abuse and diversion.

Dr. S Jain: Yeah, I'm so glad you walked us through that, Rakesh. I know in the past there have been several documentaries that have come out, articles in mainstream media, just talking about ketamine and addiction potential and consequences of that. So I'm glad we're having this conversation to just make sure we keep our eyes opened and ask all the right questions.

All right. Here's a great question about RADs. What are the benefits to the patient for rapid acting antidepressants? And do you consider that these interventions make any long term impact on our patients' outcomes?

Dr. R Jain: Another set of very good questions, and the things I'm about to share with you are rock solid science. In psychiatry, a lot of things are hypothesis based, but what I'm about to share is not hypothesis. It's settled science.

Yes, the quicker you get rid of depression, the better off the patient is. Now, that statement, if you just listened to me, sounded so trite, and you're probably going, duh. But the science actually backs it up. The longer the duration of the depressive episode, more difficult it becomes to get rid of it. It's a little bit, Sandra, like having weeds in your yard. If the weeds have just arrived a week ago and they're relatively of a certain length, it's easier to unplug them. If you allow them to settle in, they've create roots, don't they? They kind of spread out. The same thing seems to happen with major depression at a biological level, at a psychological level, and at a social level.

Depression, if persistent, literally teaches the patient how to continue maintaining it through changes in cognition, through changes in ways individuals think or cope with stress. And of course, socially and functionally that is the case. The longer the depression, the greater the impairment. So for all those reasons, biological, psychological, social, to get rid of depression as rapidly as possible is appropriate. And that's why RADs are so interesting.

And one final element, just in case any of our listeners are still sitting on the fence, appreciating the value of RADs. If one gets rid of depression fast, the long term benefit is that relapse and recurrence rates are actually diminished. They're actually diminished. So by just doing something right at this time, which is rapidly get rid of the depression, there are long-term, way long-term potential benefits to the patient and to their families.

Dr. S Jain: Rakesh, as I'm sitting and listening to you talk about this, what comes to mind is treatment. The timing of treatment for people who have diabetes, whether it's type two or whether it's type one, that without treatment, fast, quick interventions, just slight changes in A1Cs add to or take away from long-term complications. Do you think that's a fair comparison to what you're talking about?

Dr. R Jain: I think, it's more than fair. It's far on accurate. It's a very good example you use, because it's so tangible, and I think the metaphor that you used may be one that our colleagues listening to us could also use in their clinical practices.

Dr. S Jain:Yeah. All right. Questions about antidepressant combinations. Clinicians are wanting to know, does the combination work faster or better than monotherapy?

Dr. R Jain: It depends on which antidepressants you're combining. So, the bad news is if you're combining the classic monoaminergic antidepressants, I'm afraid that data is not persuasive. It doesn't seem that if you just keep flogging the serotonergic system, or the noradrenergic, or dopaminergic, it automatically hastens the arrival of response or remission.

But what is interesting? Now, thanks to a RAD that was released by the FDA, only very recently, and that is the combination of dextromethorphan and bupropion. That is a combination medication, but the mechanisms are quite different. Bupropion, of course, is a norepinephrine and dopamine reuptake inhibitor. Dextromethorphan is an NMDA receptor antagonist. And that particular combination, which by the way is available to us and our patients under the brand name Auvelity, has actually demonstrated clearly and convincingly a rapid onset of action in ways that are incredibly surprising, positively surprising.

So the answer to that great question is, yes, combination of antidepressants can hasten the arrival of response remission, but it really matters which antidepressants you're combining. It's not like, any antidepressant combined, it's going to work.

Dr. S Jain: Got it. All right. Here's another great question with GABA agonist interventions. Clinicians are asking, don't I need to worry about addictions really in the same way that we're worrying about addictions with benzos and Z-drugs?

Dr. R Jain: Yes, we are worrying about it, and I think because we didn't worry about it enough 10-20 years ago, is why we are in this pickle in American society, which is GABAnergic medications that are effective. Yet, the diversion abuse dependence issues are significant. So the question is such a fair one. What about this new class of drugs? Will I have the same problems?

Well, I have two things to share with you, colleagues, that may actually diminish your concerns considerably. Number one, the new class of GABAnergic medications don't actually look like benzodiazepines at all. So just to be technical for a second, and to repeat myself from what I shared during the actual video of the slides, benzodiazepines work inside the synapse. So we think of them as intrasynaptic, inside the synapse, GABAA positive allosteric modulators--oh my God, that is such a mouthful. But pretty much what they do is they increase the activity of GABA inside the synapse. The new ones are different. They do that, but they also are extra synaptic. So the differences are there.

The other is, these new mechanism of action, GABA medications, we will not be using on a continuous basis. The thought is these neuroactive steroids, these medications we're talking about, we will use highly episodically, Sandra. So at the moment it seems like, using Zuranolone as an example, we will use it only for two week stretches, and after that, the patient will not be using that medication possibly for weeks, months, even a whole year out.

So just the decrease in frequency of use of these medications would mitigate the risk. And obviously now, that we're all cognizant about risks, we'll be watching it much closer.

Dr. S Jain: Yeah, this is interesting to think about the infrequency of the use of these new medicines. And I'm wondering, Rakesh, what comes to mind is, how do we begin to educate this whole new way of thinking about treatment of major depression, not chronic long term. A lot of times when patients, I know they would come to me after seeing someone like you, and they would say, "I've got information for my depression because of what's going on. Maybe 18 months just to get things reset." But we know that many of our patients have taken these medications for much longer than 18 months, like a lifetime. How do we as prescribers, clinicians, begin to change how we think about these interventions?

Dr. R Jain: Perhaps this is what I will share, Sandra. A paradigm shift is happening right under our watch. This is a completely different way to think about and to treat depression. So how do we go about making that change? First of all, it's conversations like we're having right now, presentations like we just had a second ago, where I was able to present to you a completely different paradigm. The paradigm in psychiatry since 1950s has been the only way to control depression is to be on your medications on a continuous 24 hours a day, 365 days a year. Continuous, no break from it. And that led to some challenges. Okay, that's not true. It led to a lot of challenges. Adherence became a challenge, side effects became a challenge, and of course, relatively low rates of response and remission became a challenge.

When I say paradigm shift, look at the dramatic shift that's occurring. We are abandoning in some ways, not entirely, but to some degree, the monoamine approach to helping patients. We're moving into the GABA glutamate axis. Number two, instead of thinking that the medication must be present on the receptor 24/7, what we are saying is, and the evidence is supporting it, is you can intervene for short periods of time. For with esketamine, for example, you're intervening just either twice a week or once every two weeks. With Zuranolone as an example, the intervention will only be for two weeks, and then absences for weeks or months, perhaps even longer. That may be sufficient to reset the biologic, psychologic, and social system in the person that we do not need necessarily to be on continuous therapy. A paradigm shift is happening and it couldn't happen fast enough, because patients and we really need something different.

Dr. S Jain: Yeah. Beautifully stated. Rakesh, we have about a minute and a half left during Q and A, which isn't enough time, but I'm going to toss in one more question. Clinicians are wanting to know, and your advice about, is there a way to distinguish who might benefit best from a RAD versus SSRI or an SNRI?

Dr. R Jain: Right. Happy to address that. At the moment, we are very fortunate to have two approved RAD treatments and more on the way very soon. The two approved RAD treatments are, of course, Spravato, which is esketamine, and Auvelity, which is the combination of dextromethorphan, which is also an NMDA receptor antagonist, and bupropion. We already have that. It's not like, these are all ideas. So with esketamine, we are not allowed to use it first line. So there, the case is already made that you really do have to try SSRIs first or SNRIs first, at least two of them, actually. So it's not a matter of this or that, you can use it in combination. But in terms of the dextromethorphan plus bupropion combination, that's actually approved for the treatment of depression. So it could be used first line, second line, or a hundredth line.

There the issues are more dependent on what are the patients' needs, what are their desires. I've never met a patient who says, "Why don't we just take four weeks or six weeks to get my depression better?" Invariably patients say, "The sooner, the better." So considering these RADs earlier would be appropriate. Though I have to be also realistic, access is sometimes an issue, and often the insurance companies may ask us to go through a trial or two of an SSRI, SNRI. But that's okay, we don't have to wait years before a patient accesses a RAD. It's okay to, perhaps, get to it within two or three months.

Dr. S Jain: Yeah. Got it. Well, sadly, we are at time. I wish we had more, but I want to thank our attendees, because really some great questions. And thanks to you Rakesh, for your interesting presentation on RADS. So I want to invite everyone, please join us for our next session of the day. And just like before, that one's going to be starting in about 15 minutes.