Emerging Treatments in MDD


Experts in psychiatry review emerging mechanisms of action in the treatment landscape of MDD.

Andrew J. Cutler, MD: We’ve talked a lot about recognizing depression, how we set expectations, how we involve our patients in our decision-making, and how we select from the available therapies. Let’s talk a bit, Greg, about some of the excitement on the horizon with some of these newer emerging treatments. Which of the newest treatments are you most excited about? Just asking in general, and then I’ll throw out some specifics.

Gregory Mattingly, MD: Andy, I think the better question is which new mechanism am I not excited by? We’re doing trials right now of, I think, 8 different mechanisms, slightly different places where we’re hitting that glutamate/GABA [gamma-aminobutyric acid] cascade. I think they’re all going to have a fairly fast onset, Sagar. The good news is it looks like all of these novel mechanisms have fairly fast onset; some of them are going to avoid dissociation. We haven’t seen that with some of these. Some of these are going to allow intermittent dosing. In one of the trials we’re doing, you take your medicine once a week. It’s an oral medicine that you take once weekly. We’ll look at how we reset some of these mechanisms, but primarily around that GABA/glutamate cascade within the nerve cell.

Andrew J. Cutler, MD: Greg, that’s fascinating because we’re not only talking about new mechanisms of action, as we’ve been saying here, but we’re talking about new treatment paradigms. The idea of something that acts more rapidly, maybe something that we only have to treat for periods intermittently. I think that changes how we talk to our patients, how we set expectations, and how we monitor. We don’t wait 6 weeks to do our PHQ-9 [Patient Health Questionnaire-9 item], for instance. Sagar, what are you most excited about?

Sagar V. Parikh, MD, FRCPC: There are several different things. I think the whole IV ketamine business has spawned a tremendous resurgence in looking at different mechanisms. The ketamine story continues to unfold. Whether it’s the R-ketamine [racemic ketamine] or S-ketamine [esketamine], whether it’s metabolites of ketamine, ketamine-like substances, and of course, which receptors are being tickled and to what extent. That’s one very encouraging thing. The second thing is, I think a paradigm shift, where we are returning to what are maybe historic roots and the role of psychotherapy integrated with medication. When we think about psilocybin and psychedelics, it’s not a standalone treatment. It’s not 1 pop of the mushroom and off you go. It’s integrated with a coherent, manualized psychotherapeutic preparation, an 8-hour psychotherapy journey during the day of the magic mushroom, psilocybin kind of ingestion, and some consolidation sessions afterward. We’re also seeing that in PTSD [post-traumatic stress disorder] with the administration of certain compounds, whether it’s D-cycloserine or other things, newer things, with the psychotherapy for that. This reintroduction of multiple mechanisms I think is really exciting.

Then combining modalities; we already made some reference to digital tools, like digital CBT [cognitive behavioral therapy] tools. I’m aware of a trial going on where there’s an artificial intelligence bot, which is going to be integrated and layered on top of regular medication treatment for postpartum depression. But the women will also get CBT through this artificial intelligence device, which automatically converses with the patient and addresses negative cognitions and things like that. There are all sorts of twists and turns in terms of how to integrate traditional treatments with digitally delivered treatments.

Then the final one, which we mentioned very briefly at the beginning, was new protocols for doing transcranial magnetic stimulation [TMS]. We saw that the FDA approved a new form of TMS called Theta Burst TMS a couple of years ago. And that was primarily done out of some studies out of Canada that showed Theta Burst was equivalent. Three minutes of TMS by Theta Burst was equivalent to about 40 minutes of traditional TMS treatment. That really sped up the treatment session. We most recently saw the FDA approve a new TMS protocol 10 times a day for a week out of a protocol pioneered at Stanford University, and people were much better. I see so many different mechanisms and so many different approaches, and I see a lot of integration and overlap.

Finally, there’s something old that’s new again, and that is about 10 years ago, an Australian company developed a video game for adolescents. The game took the principles of CBT and made negative thoughts the bad guys in the video game that you had to shoot down or something. They were able to show that adolescents playing this video game internalized the lessons of CBT and got better in their depression. Now, for unclear reasons, that game never got commercialized, but I’ve heard and I’ve seen some more recent examples of things emerging in that way. So, we’re going to have video games that will be very engaging, particularly for teenagers, that will still be relying on our core principles like CBT principles but will be delivered in a way that is both scalable and highly appealing to the target audience.

Andrew J. Cutler, MD: Therapeutic video games, Greg and I have been involved in the development of one such modality for ADHD [attention-deficit/hyperactivity disorder]. There’s one on the market for that. I think you’re right about the use of technology. Greg and I also a few years ago wrote an article called, “Beyond the Pill.” I think our idea here was to think about all the different kinds of treatment modalities beyond, “Here, take 2 pills and call me in the morning,” if you will, traditional treatments.

I’m also fascinated by something else. When we talk about these new mechanisms, we talk about the NMDA [N-methyl-D-aspartate] receptor antagonism, which is how we think ketamine works. There are a variety of these others. There’s one in development called S-methadone, which is one of the isomers of methadone that does not have much μ-opioid agonism, it’s an NMDA antagonist. It turns out that, like everything else in life, it’s all about moderation. You can block the NMDA receptor enough to be an antidepressant, but if you block it too much, you get dissociation. The dissociation is toxicity, it’s not necessarily a therapeutic benefit. There was a real controversy around that, it was thought you might need that. And the same may be true with psychedelics. We don’t exactly know, but it could be. A lot of people ascribe some of the therapeutic benefits to the hallucinogenic experience, the psychedelic experience of the trip. There are second-generation psychedelic medicines in development that through an intracellular process called biased agonism actually don’t give you a psychedelic trip, but still activate 5-HT2A receptors and appear to at least induce synaptogenesis in animal models.

We have to stay tuned and think about this whole experience here. Maybe it’s all about individualizing the treatment for each patient. As you mentioned earlier, it’d be great if we had some biological test to match these new treatments to the right patients.

Transcript edited for clarity

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