Gregory Mattingly, MD

Experts comment on emerging treatments for anhedonia and highlight lifestyle modifications that support patients with Major Depressive Disorder.

Emerging Treatments of Anhedonia in Patients with Major Depressive Disorder

In addition to the dextromethorphan-bupropion combination, the clinicians review other evidence-based treatments for anhedonia. These include medications modulating dopamine, glutamate, kappa opioid receptors, and psychedelics. Lifestyle approaches like exercise, diet, sleep, social connection, and purpose are also critical, improving motivation and pleasure by enhancing BDNF, endorphins, and dopamine while decreasing inflammation.

They emphasize assessing and tracking residual symptoms like anhedonia even in patients considered asymptomatic or “in remission” on rating scales, as lingering lack of enjoyment, drive, or interest predicts later recurrence and dysfunction. Using practical measures of life engagement and specific hobbies, relationships, or tasks is recommended over formal rating scales to identify ongoing areas of impairment.

In closing, the clinicians express excitement about the expanding treatment options to address unmet needs like motivation and pleasure that have been resistant to standard interventions. They urge clinicians to utilize both new tools emerging from ongoing research as well as digital measures and benchmarking to ensure treatment gets patients to optimal functioning, not just minimal symptom reduction. Keeping skills updated and identifying patients struggling with residual symptoms is key to enabling fuller recovery.

This summary was AI-generated and edited for clarity. 

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Dr Andrew Cutler and Dr Greg Mattingly comment about emerging treatments to treat anhedonia and highlight lifestyle modifications that support the wellbeing of patients with Major Depressive Disorder.

Dr Greg Mattingly shares his view on major challenges in the management of Major Depressive Disorder and limitations of medications currently used.

Limitations of Current Treatment Options for Depression

The clinicians identify major challenges in diagnosing and managing depression, including inadequately addressing symptoms like anhedonia, cognition, and motivation that drive disability. Current antidepressants like SSRIs often don't improve these hard-to-treat symptoms. SSRIs also worsen cognition by decreasing dopamine. Another limitation of SSRIs is their delayed therapeutic benefit, taking 4-6 weeks to relieve symptoms despite increasing serotonin right away. This delay contributes to increasing depression rates and disability.

Additionally, SSRI side effects can limit long-term treatment adherence. While patients tolerate short-term side effects, ongoing effects like weight gain and sexual dysfunction often lead patients to discontinue treatment.

Given these SSRI limitations, Drs. Cutler and Mattingly emphasize the need for faster-acting antidepressants that provide “pan-symptom improvement” beyond mood, including motivation and cognition. Promising options may target glutamate signaling or activate overall neural networks more rapidly.

In summary, while SSRIs are the standard depression treatment, they fail to address all symptoms and have a slow, limited response plus troublesome side effects for many patients. More effective, rapid-onset antidepressants with better side effect profiles are critically needed.

Summary was AI-generated and edited for clarity.

While we’re waiting for these new treatments to come about, let’s talk a bit about, how can we improve adherence to our treatments, and awareness and communication and education of our patients and our colleagues? Greg, you’re certainly a master educator and communicator. What advice would you have?

: I think one of the keys is breaking down stigma. There are stigmas with all of our health conditions, including depression. I was part of a study recently, Andy, where we asked patients, “Where do you face stigma when you’re battling depression?” And a significant chunk, about 1 in 5, said they had internal stigma. “I beat up on myself about having this condition.” Those feelings of, “I’m lazy, dumb, stupid…get up off the couch. Also, there’s stigma in my society. People around me may not understand why I have depression. How come you’re not doing those things?” The biggest place of stigma was occupational stigma. For patients struggling with depression, 83% said, “I face stigma or perceive stigma in the workplace.” It’s OK to tell my employer I need to take a day off because I’m having asthma attacks. It’s OK to tell them I’ve had a flare-up of my arthritis, I’ve got to get some steroids. Most people are reluctant to tell their employer, “I have to take a day off because I’m struggling with depression and I need to go see my mental health provider.”

Breaking down that mental health stigma is part of a couple of initiatives right now with One Mind. The One Mind at Work initiative is working with employers across the country to break down mental health stigma within the workplace. Putting in engagement paradigms, where it’s OK to come and ask for help. We want you to be at a healthy workplace. We know it’s one of the biggest causes of disability within our workplace, and if you’re struggling with this, please come in and get help. I think those are some of the really important initiatives right now.

: Sagar, what do you think are some misconceptions out there among our colleagues in various disciplines of medicine? What are some of the needs that they might have in better understanding depression?

: I’m a little more optimistic. I think there have been a lot of antistigma efforts over the years. There’s been a lot of attention on depression at health care providers. While there is stigma across a lot of mental disorders, I think for the most part, most clinicians are understanding depression as a real thing, and as something worthy of treatment, and not a particularly shameful thing. I will go down on the side of optimism and positivity and say we’ve made progress in stigma. Where we saw, and where Greg started us off was commenting on the tsunami of depression because of the pandemic and everything like that. And as we already knew, the particularly vulnerable people are adolescents.

I think our strategy should be let’s go where the action is. I’m really happy to say that at the University of Michigan, we’ve had 2 major programs that are delivered in high schools. One program teaches principles of CBT [cognitive behavioral therapy] to teachers and other educational providers right in the schools. The second program is directly aimed at the students themselves, and it mobilizes students to create depression awareness programs for their own school. These work in complementary ways. One works on teachers and principals and things like that. In the old way of thinking when we were in high school, we went to gym class to learn the basics of physical fitness. So, why don’t we do that with mental health? Why don’t we start not only shooting a basketball, but also shooting down negative thoughts or learning some other mental health skills? Learning some CBT skills informally, before we’re clinical, in high school as a prophylactic against future depression. Simultaneously, address the issues of any potential stigma through other kinds of awareness, so that adolescents early in the course of illness, maybe we prevent some, maybe we delay some illness. And when the illness occurs, they are motivated to get treatment quicker.

That’s really exciting, Sagar. I love the idea of reaching out and being proactive, and like you said, getting to the source and meeting people where they already are. I suppose that kind of program could also be done in workplace environments and other areas. Greg, as we wrap up here, what would you say are some of the remaining unmet needs in recognition and/or treatment of depression?

: Once again, depression is nobody’s fault, and depression doesn’t discriminate. We’ve all had friends, family members, loved ones, people we know who have been touched by depression. I think prescribing with hope, Sagar’s comment about being optimistic with our patients, relating to them as people, not just as illnesses. “Who are you, what’s important to you? What are your values? What’s this journey together as we go through it?” I think that’s the exciting thing. Then for those of us who are clinicians, let me just say, it’s never been a more exciting time as far as all the things right now that are in development: digital interventions, therapeutic tools that have totally different mechanisms of action, treatments that can be taken as needed instead of on a chronic treatment basis. It’s an exciting time to be in neuroscience.

I want to thank you gentlemen for this rich and informative discussion. Before we conclude, I’d like to get final thoughts from each one of you. Greg, what would you like to leave our audience with when we’re thinking about depression?

: I’m going to go back to a common theme in our talk today, and that’s hope. There is hope for our patients who have been struggling. There’s hope with medicines that have novel mechanisms of action. There’s hope to move the needle in ways we haven’t been able to, with our use of digital tools, and digital therapeutics. Hope would be what I’d leave the audience with.

: I’d say to our clinicians, be proud of the work that you do, no matter what the environment was when you were a kid and maybe your parents said, “What? You’re going into psychiatry?” You know what? Our turn has come. Society has accepted that mental illness is real, and there are a variety of strategies that can be helpful. And the work that we do, the work that you do, is critical to the individual and society, so be damn proud.

Sounds great, and I’d add one final thing. I think it is very exciting that we’re developing these new tools, and ideally, we’ll be able to do a better job of individualizing and personalizing our treatments, just like people do in other fields of medicine.

I want to thank you too, our audience, for watching this 

. If you enjoyed the program, please subscribe to our e-newsletters to receive upcoming programs and other great content right in your inbox. Thank you.

Andrew J Cutler, MD; Gregory Mattingly, MD; and Sagar V. Parikh, MD, FRCPC, comment on the need to improve awareness around depressive disorders and break the stigma of mental health treatment.

Improving Awareness for Depressive Disorders

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.

: 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.

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?

: 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.

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.

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

Gregory Mattingly, MD

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