New and Exciting Treatments on the Horizon for MDD

In this Q&A, Craig Chepke, MD, DFAPA, medical director at Excel Psychiatric Associates, shares his thoughts on breakthrough treatments that are transforming treatment approaches to major depressive disorder (MDD). He delves into the promising results he's witnessed with the dextromethorphan-bupropion combination and discusses innovative treatments on the horizon, such as kappa receptor antagonists. Discover how these emerging treatments could enhance patient outcomes while minimizing side effects, providing renewed optimism in the journey toward mental health.

Answers have been lightly edited for clarity.

DepressionCare 360: Can you discuss some new and emerging treatments for major depressive disorder (MDD) that you're particularly excited about?

Craig Chepke, MD: Major depressive disorder is a condition that no matter how many new treatments we get, there's always going to be unmet need. One new treatment that's been out for a couple of years that I've really been excited about is the combination of dextromethorphan and bupropion. It had great clinical trial data, and in my clinical practice, I've had good results with it and seen some benefits quickly. It's a rapid-acting antidepressant with efficacy as short as one week in the trials, and I'm seeing that in practice as well. People are starting to notice a benefit, and it does continue to grow over time, so you don't get the full benefit right away, but people seeing a benefit early on encourages them and gives them some hope, which is the most important thing. People with MDD need to continue their treatment and then see the greater benefits as time goes on.

We've got some new treatments coming up in the pipeline, hopefully in the near future. Some agents that I'm excited about are kappa receptor antagonists, which are part of the endogenous opioid system. Opioid may sound scary, but these are antagonists of the kappa receptors, and what we believe happens when kappa receptors are antagonized is that they can release dopamine into the striatum, where the reward system is localized. These treatments are usually targeted toward people with anhedonia, one of the core symptoms of MDD. 

However, anhedonia is often very poorly treated by our traditional first-line antidepressants, SSRIs, etc. Not only are they poorly treated, but they're often very residual as well, so even if we do treat the emotional and physical symptoms of MDD, anhedonia is often leftover, and we don't have any good evidence-based treatments for addressing it pharmacologically. There are some things that we use off-label that are typically dopaminergic—bupropion would be the most common one, but there's really no good high-quality evidence for that. In practice, I don't see good results in terms of anhedonia for something like bupropion. However, the kappa receptor antagonists are a pretty good degree of data. There's a portfolio, so to speak, of data that's been generated from some phase 2 studies showing fMRI activation of the ventral striatum by use of one kappa antagonist called aticaprant. That has been backed up by that phase 2 study, shown clinical efficacy in the depressive symptoms, and using the Snaith-Hamilton Pleasure Scale (SHAPS), specifically a measure for anhedonia. Then a second follow-up phase 2A study again demonstrated clinical efficacy in both depressive symptomatology and anhedonia symptoms as well.

There's another kappa antagonist called Navacaprant, which also has one positive phase 2 study and phase 3 studies coming later in 2024. These could be coming into our arsenal in the clinic within the next few years. The best part is they're very well tolerated in general low side effect burden, very low discontinuations due to side effects, and, importantly, no weight gain or sexual dysfunction caused by these agents, which are the 2 "dealbreaker side effects," as I call them in my practice. 

Craig Chepke, MD, DFAPA, is a board-certified psychiatrist in clinical practice as the medical director of Excel Psychiatric Associates in Huntersville, NC, and is an adjunct associate professor of psychiatry for the Sandra and Leon Levine Psychiatry Residency Program at Atrium Health. He attended NYU School of Medicine and completed his psychiatry training at Duke University. As part of an interdisciplinary treatment team in his practice, he employs a person-centered care model to tailor treatments to each individual's needs, integrating traditional pharmacotherapy with psychotherapeutic and physical health and wellness interventions. His clinical and academic interests include serious mental illness, movement disorders, ADHD, and sleep medicine. Dr Chepke is the scientific director for the Psych Congress portfolio of CME conferences, and he has been recognized as a Distinguished Fellow of the American Psychiatric Association.

© 2024 HMP Global. All Rights Reserved.
 
Any views and opinions expressed above are those of the author(s) and do not necessarily reflect the views, policy, or position of the Psych Congress Network or HMP Global, their employees, and affiliates.