Challenges With Traditional MDD Treatments

Andrew J. Cutler, MD: We still have challenges. Sagar, what are the limitations of some of our traditional antidepressants here?

Sagar V. Parikh, MD, FRCPC: I think the biggest limitation is everything works slowly. And we’re in the TikTok generation, so we have 15 seconds to show an effect. Can we at least have maybe 15 days or something like that? It’s very hard to tell somebody they have depression because instead of saying, “Take 2 of these and call me in the morning,” it’s more like, “Take 1 of these and call me in 6 weeks.” And that’s terrible to have to tell patients that the main effects of their antidepressant won’t kick in for 4 to 6 weeks and perhaps 8 weeks.

So I think our No. 1 need is we need things that work quickly, and we’re starting to see some progress there, both with medications and recent publications and [with] the recent FDA approval of a newer form of transcranial magnetic stimulation, [with which] you can have multiple treatments per day and can be better in a week. But we’re also seeing that with the newer medications; IV [intravenous] ketamine is a good example where the improvement is pretty fast acting for most people.

So rapidity of action is, I think, what we need most of all. I think people would put up with adverse effects if they knew that they’re going to get better faster. But of course, the calculus changes once you’re starting to feel better. You’re no longer willing to put up with adverse effects. When you’re really feeling miserable, you’ll say, “I’ll put up with anything to have some improvement.”

So, after rapidity of action, we need a real nice tolerability profile, especially for medicine that is chronically used. Or if we could even have a treatment that you could have for a short period of time and then you’re well—similar to having antibiotics or maybe a burst of steroids for your arthritis, and then you’re off your steroid for a while and you remain well for weeks.

Andrew J. Cutler, MD: That’d be great. Certainly, the rapidity of action would be great. Greg, how often do our medications get people into remission? How often do they work and for whom?

Gregory Mattingly, MD: Unfortunately, not as often as we would like. And that’s why in some ways we’ve been losing this slippery battle to depression; stress has gone up in our society, and we live in a digital world where cognitive capital is incredibly important. I sit right next to a GM [General Motors] automobile plant, Andy, and their jobs used to be manual. Now they work with robotics and computers.

If your brain is stuck in a depression, it’s a bigger impact on your overall daily existence. When we look at our medicines for depression, be it STAR*Dhere in the United States or very similar studies done all around the world, we know our...first crack with a standard antidepressant is going to get about 1 out of 3 people in remission. About half will respond, and about 1 in 3 will go into remission. And we know that if you’re that unlucky group that doesn’t go into remission after your first hit, then it’s a downward slope. By the time you’ve tried 2 or 3 antidepressants, those rates of going into remission are probably around 15% to 20%. So it’s not zero. A 20% chance of getting remission is better than zero. But what if this were your wife, and she had breast cancer?

Andrew J. Cutler, MD: Not good.

Gregory Mattingly, MD: What if I said, “Listen, I have a 1 out of 3 chance this medicine may get breast cancer in remission”? And as Sagar said, we have to give it 6 to 8 weeks, and 1 out of 3 patients after 6 or 8 weeks doesn’t seem like a very good hit rate. So a lot of the studies we’re doing these days are on how do we help to up those odds.

Andrew J. Cutler, MD: And even when people do respond, we still have residual symptoms. Our current medications really don’t work for the whole range of symptoms. What are some of the most common residual symptoms?

Gregory Mattingly, MD: Cognition, anhedonia, emotional blunting, sleep. All of those are very common residual symptoms.

Andrew J. Cutler, MD: They sure are.

Gregory Mattingly, MD: I’ve done a lot of research, as you know, on the cognitive domain of depression, looking at how we move the needle on things like processing speed and working memory. Anhedonia or emotional blunting is very interesting because if you don’t feel pleasure, you tend not to have reward and motivation. So if you look at our patients who don’t feel pleasure, they’re left emotionally blunted; they’ll persist on an easy day, but they give up on a hard day. And they show up in your office, and they want a job note. They’ve just dropped out of the workplace. They’re having a hard time functioning. Sagar, I’d be curious what you think, but I think cognition, anhedonia, and don’t forget, sleep are incredibly important.

Andrew J. Cutler, MD: I totally agree. What do you think, Sagar?

Sagar V. Parikh, MD, FRCPC: No, I think those are really the main ones. But there is also a sequelae to those symptoms. So there’s a lack of confidence. So you start off with the intense negative rumination of depression. Maybe you’re feeling better, you’re not as negatively preoccupied, and you’re not beating yourself up with negative cognition. However, you’ve lost your confidence. And so you’re hesitant about going back to work if you took time off work. Even if you are at work, you feel emasculated or something, and you don’t want to boldly lead or be the person in the group that says, “Hey, I’ve got a better idea for our business” or things like that. So a lack of confidence is something that I see as sequelae. It’s not technically a residual symptom, but I would say more sequelae and then tiredness or lack of energy. And again, this is a juxtaposition of whether is it a residual symptom of depression or many of our psychiatric medicines are sedating—so which one is it?

Andrew J. Cutler, MD: And the selective serotonin reuptake inhibitors can cause emotional blunting but also fatigue. I want to come back to something I mentioned briefly that we didn’t really get into deeply: adherence. And of course adherence is affected by lack of efficacy. If the drug doesn’t work or takes too long to work, that patient might give up on it. But also, adverse effects. Greg, what are the adverse effects that most commonly affect adherence? You alluded to this before.

Gregory Mattingly, MD: Andy, thank you for bringing that up. A lot of our support networks—the Depression and Bipolar Support Alliance, which is a wonderful advocacy group for people with mood disorders—when you talk to their members and ask what they like or don’t like about our current treatment options, we tend to think about efficacy, but they tell us about adverse effects. They’ll say the most troubling part of our current treatment options is almost all of them come with baggage that makes it very hard to keep taking them on a consistent basis.

So then you ask, “What’s the baggage there?” You see weight gain, sexual adverse effects, sedation, emotional blunting, and then sometimes agitation. If a medicine makes someone restless, that tends to be a deal breaker very early on. A lot of those other adverse effects are deal breakers down the road, as Sagar said. “I’ll put up with them at first, but I’m not going to put up with them in the long run. I’ll put up with not being able to be intimate with my partner for a week or a month, but eventually, I want to feel like I can be in a relationship again.”

Transcript edited for clarity