Andrew J Cutler, MD; Gregory Mattingly, MD; and Sagar V Parikh, MD, FRCPC, discuss clinical data on zuranolone from the WATERFALL, CORAL, and SHORELINE studies for the treatment of major depressive disorder.
Andrew J Cutler, MD: There was a study called CORAL, Sagar, where zuranolone was added to a standard antidepressant, and they showed faster onset of action than the antidepressants alone. It sounds like that might be helpful as well.
Sagar V Parikh, MD, FRCPC: What’s useful about that is when we think about studies, we don’t live as clinicians. We don’t live in a world where we put people on a placebo. We don’t live in a world where we generally strip them of all their existing treatments and then start a brand new treatment. We often layer on things. We try to prune a little bit before we start something new, but we often say, “I think the person’s getting some benefit from their existing regimen. They’re not well yet, so I need to add something.” What I liked about the CORAL study is that mimicked what I think is real-world practice. They used a number of standard antidepressants, mostly SSRIs [selective serotonin reuptake inhibitors], and a couple of SNRIs [serotonin and norepinephrine reuptake inhibitors], and asked does it help to use zuranolone in combination. And it did. It speeded up the response. In a way, you satisfy everybody because the low and slow people are like, I don’t know, I don’t want to give up the traditional time-honored medicines. OK. So, stay on it, or start a standard older treatment, but to jumpstart your improvement, you can benefit by adding some zuranolone as well.
Andrew J Cutler, MD: Greg, it’s interesting, this drug now has been studied for MDD [major depressive disorder]. Again, not TRD [treatment-resistant depression], although it might be used for that. It’s been studied as monotherapy. It’s been studied and added to antidepressants. The SHORELINE study that you and I were involved with took people who either were on an antidepressant or not and added zuranolone. It seems that the mechanism predicts so this might be helpful for some of those things we talked about earlier for sleep and anxiety, working through the GABA-A system. Very often, we add things to help with sleep or anxiety, maybe a benzodiazepine or hypnotics. So here’s a medicine that maybe is helping the core depression as well. What do you think of that, clinically?
Gregory Mattingly, MD: Once again, I think it goes back to the mechanism of action and this is working through GABA. The side effect, you can predictably get, and my patients have told me this, that first night or 2, it’s going to make you sleep. Get ready to sleep because that’s one of the adverse effects of this medicine. But that may be part of why it’s restorative as well; getting circadian rhythm back, getting a good night’s sleep. And then helping to reset that thermostat for why people have depression, I think it’s part of the mechanism here. And then, I love Sagar’s idea that we use this as part of a holistic treatment paradigm. That neurobiology of resilience, how do we help to get you healthy? How do we get you resilient? How do we get you well; exercising, socially connecting, thinking about your cognitive biases and where you get in your head and ruminate. Let’s work through those things. And Sagar, my favorite type of therapy isn’t cognitive therapy or behavioral therapy, it’s what I call self-esteem therapy. How do we help your damaged self-image? How do we help repair that and get that back to where it should be?
Andrew J Cutler, MD: Well said. It’s very interesting here that we’re talking about not only a more rapid-acting paradigm here with zuranolone, we’re also talking about this episodic treatment paradigm. And it’s theoretically possible, isn’t it? That we’re resetting? I talked a little bit earlier about networks and circuits. And maybe we’re resetting some of the circuitry in the networks. That’s one of the theories now about some of these rapid-acting medications as well.
Transcript edited for clarity