Spray Away Severe Depression

When severe depression becomes treatment-resistant depression, an unconventional medication is proving to be effective. It’s a specific form of ketamine that is administered by nasal spray in a supervised clinical setting, approved by the FDA for this purpose. Dr. Caleb Battersby, director of interventional psychiatry at UConn Health, explains how esketamine works and why this treatment approach has been providing hope for those who otherwise may be out of answers.

(Dr. Caleb Battersby, Carolyn Pennington, Chris DeFrancesco, April 2025, studio and technical support by Ethan Giorgetti and Ryan Bernat)

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Transcript

Chris: Depression has all kinds of medicinal options. Today on the Pulse, we focus on what happens when those medications don’t work.

This is the UConn Health Pulse, a podcast to help you get to know UConn Health and its people a little better, and ideally leave you with some health information you’ll find useful.

With Carolyn Pennington, I’m Chris DeFrancesco. Severe depression becomes treatment- resistant depression when medications aren’t effective.

Carolyn: But a combination of behavioral therapy and a nasal spray is showing promise in adults who are in that situation. Joining us today to explain is Dr. Caleb Battersby, director of interventional psychiatry at UConn Health. Thank you for your time today.

Dr. Battersby: Thank you.

Carolyn: Now a nasal spray may seem like an unconventional way to treat depression, so let’s start with that. How does that work?

Dr. Battersby: We have patients who come to the hospital for this treatment. They have to be in a monitored setting for a couple hours. And the nasal spray functions like any, like a saline spray or Flonase or something like that, patients self administer it.

The advantage of a nasal spray is that it does have a quicker onset of action compared to something that you’re taking orally. And especially in the case of esketamine, which has its own kind of quick onset of action, it just allows that medication to work better and work faster.

Carolyn: Why do they have to come to the hospital though? Why do they have to be monitored?

Dr. Battersby: Esketamine and ketamine, generally, the psychoactive effects can be concerning for patients, so dissociation or an out-of-body sensation, sedation, sometimes people can become anxious with the treatments or have an adverse reaction like that. We also like to monitor patients’ blood pressures, which can increase with the treatments.

So in addition to the fact that ketamine and its analogs are potentially abusable compounds, when the FDA approved esketamine, they felt like it was warranted to have the patients also have to come into the hospital to get monitored during those treatment sessions.

Chris: It seems as though — so esketamine is the version we’re talking about with the nasal spray. You’ve also mentioned ketamine. They sound alike, they’re related, but there are very important distinctions in this application, correct?

Dr. Battersby: Right. So the initial research that was done with ketamine for depression was done with the IV form of it. And it was shown to be rapid and quite effective, even for patients who hadn’t responded to other treatments.

The IV form of ketamine, there are clinics that are around, but you typically have to pay out-of-pocket because insurance doesn’t cover it. So esketamine, it was developed by Janssen, it’s been approved by the FDA for treatment-resistant depression, so it is covered by insurance. And so that’s, that’s why we’re kind of leaning towards that option, it allows patients to access the treatment without having to pay too much out-of-pocket.

In terms of the differences with the treatment effects, they are pretty similar. The IV ketamine, again, it’s going through an IV, so it’s more bioavailable than the nasal spray, but it seems like their effects are pretty similar in terms of the benefits for depression.

Carolyn: Is the length of using it the same, as far as, I think, when we’ve talked before, it’s like they come in for a couple of treatments the first couple weeks and then it’s kind of tapered as they go along? Describe that whole process.

Dr. Battersby: Yeah, it’s similar. So with the es esketamine, the typical regimen is people come in twice a week for four weeks, and then once a week for four weeks, and then after that it becomes flexible, depending on their response. The studies that are out there for esketamine have followed people out five, six years. So the approach of this medication tends to be that if it’s working for you, you stay on it. There is a pretty high rate of relapse if you stop it, and so a lot of our patients either continue it on a weekly basis, or they’re able to decrease the frequency, so they come every couple weeks or, in some cases, every four weeks, or something like that.

So, compared to IV ketamine, you know, the, the regimen is largely similar. Again, the longer term treatment with IV ketamine is probably limited because patients have to pay out-of-pocket for those costs. But it generally seems like this kind of treatment, if it works for you, you probably need to keep getting it in some capacity moving forward. And that might just be on like a less frequent basis. So you come once a month or once every couple months.

Chris: Can you, if you’re in that situation, if you’ve been on it for a while, months or even years, can you graduate to the point where you can self-administer at home, or is it always going to be in a supervised clinical setting?

Dr. Battersby: That’s a good question. I think that’s typically it. It kind of depends on the practitioner. There’s a little hesitation with the ketamine at home, again, because of those psychoactive effects and the abuse potential. That being said, I mean, there’s certainly patients you work with for months, years, you build up a good relationship, and yeah, it might just make more sense to do ketamine at home. Now, you can’t do the esketamine at home, that has to stay in the hospital. So that would entail using a compounding pharmacy to get the patient either a nasal spray form of ketamine or an oral form of ketamine.

I think there’s a lot of unanswered questions about ketamine. It’s a little bit of a wild west out there in terms of kind of how to administer it, the different ways you can administer it, the best protocol, the best approach. And so we’re all kind of navigating that, but that makes it challenging and exciting too.

Carolyn: But you have said in the past that this is such a hopeful drug for so many people that had severe treatment-resistant depression that it really has unlocked so many things for them that they’re usually then better, even in talk therapy, cognitive behavioral therapy, whatever. Why is that? What’s it doing in the brain? Why do you think it’s more effective than so many other medications out there?

Dr. Battersby: It probably has a lot of different effects, but the primary focus in terms of what it’s doing uniquely compared to other medications is, it is rapidly altering the nature of the patients, the neurons and connections. So at the level of the synapse, which is where neurons communicate with one another, you’re getting more connections between those neurons as a result of the esketamine treatments. Now, those connections don’t necessarily last. They tend to fade away after a week or two, which is why patients tend to need to keep coming for the treatments. But because those connections are made pretty rapidly, it can translate into I think people being able to kind of make lifestyle changes probably more quickly and more effectively than they do with oral medications. And again, like you mentioned with like the talk therapy, like if somebody’s already in therapy, that can take on a different kind of flavor. It can become more productive, patients can gain more insight.

So it’s really rapidly changing the nature of the connections between the neurons. And we always just tell patients that you take advantage of that. So make the changes that you need to make in your life to kind of get yourself back on track.

Chris: Almost like as a catalyst to help make these other factors in your path to treatment more effective, almost like having a multiplying effect.

Dr. Battersby: Exactly. Yeah. And that’s how we, we like to phrase it that way, because, I think, we want patients to still have a sense of autonomy when they’re getting medications. So something like this is very effective for them, but we wanna make sure that they still feel like the ball’s in their court. And that it’s partly up to them to kind of make those changes that they need to make to kind of get themselves on more solid footing.

Carolyn: So we’ve been talking about people with severe depression, but what about other types of disorders, eating disorders or whatever, I mean, is this hopeful for maybe those kinds of patients down the road too?

Dr. Battersby: Yeah, I think that, the general fact that it’s affecting the connections between neurons, would translate into potential benefits of something like an eating disorder. I mean, they are kind of experimental, they’re kind of case series or case reports of patients who have eating disorders or OCD, PTSD, who do have a beneficial response to ketamine or esketamine. Not just in the fact that it’s improving their mood, but it’s also affecting these other conditions in a good way.

Chris: How do we get to the point where it’s more than just a couple of bad days, but it’s something more severe? And on the spectrum of how severe depression is, we go from depression to bad depression, to severe depression, to treatment-resistant depression, and now you’re a candidate for a treatment like this. How do we kind of measure that or recognize it?

Dr. Battersby: The patients typically, they have to meet the criteria for major depressive disorder, which is characterized as at least two weeks with a host of depressive symptoms. Most of the patients that are coming to us, they’ve been struggling for months or years with depression, and really what we qualify as treatment-resistant is if you’ve tried two different types of medications and you haven’t responded to those, then that qualifies you as treatment-resistant, at least in the context of being able to receive this medication, the esketamine. But a lot of times the patients we’re seeing, they’ve tried 10, 15 meds, they’ve tried different types of therapy. They’ve had inpatient hospitalizations, they’ve done intensive outpatient programs. So a whole host of different treatments have been tried. And that’s how they kind of land with us, because they’re at the point where they need to try something different.

Carolyn: Just, as you were talking about the different therapies, what about ECT? How does this compare with electroconvulsive therapy?

Dr. Battersby: Yes, so we offer ECT here at UConn. I think again, it’s still kind of up in the air what patients are best for ketamine versus ECT. There have been some trials comparing IV ketamine head-to-head with ECT, and it seems like the conclusions from those trials is that patients who are hospitalized, psychotic, are probably better candidates for ECT; patients who are outpatient, they don’t have any psychotic features in their depression, and probably also patients who are younger, probably makes sense to start with something like esketamine first.

In our clinic, in our patient population, we’ve had patients who haven’t responded to ECT who’ve responded to esketamine. And we’ve had patients who haven’t responded to esketamine respond to ECT. So they’re both, I think, viable options for this population. And there’s a little bit of guidance in terms of how do you select one or the other, but that’s still kind of being sorted out. It’s hard to predict these things.

Chris: In the couple minutes we have left, can you help us understand how someone finds his or her way to this type of treatment? Like, I couldn’t just announce one morning, “Nothing’s working. I’m just going to go see Dr. Battersby for esketamine.” I’m sure there’s a process and reviews and referrals and those kinds of things. So how does someone find his or her way to you?

Dr. Battersby: Well, it’s funny because some people do actually just call us up.

Carolyn: Oh, really?

Dr. Battersby: Because again, because they’ve heard us on the radio or something like that. But you do need a referral from your doctor or APRN who is managing your psychiatric care. There’s a website that’s run by the company that makes esketamine, it’s the Spravato website. So Spravato is the trade name for esketamine. If you go to that website, you can enter in your ZIP code and it will show you different treatment centers.

Luckily, in Connecticut, we have a lot of different places that offer this treatment. We have a lot of different places that offer ECT too, so we’re very lucky that we have kind of a density of treatments in this part of the country, but definitely a referral from a psychiatric provider, and of course you can look up the locations of these clinics online.

Carolyn: Do you think maybe just overall, have you really seen an increase in patients?

Dr. Battersby: Yeah, I think so. It was released prior to the pandemic. It was approved in 2019. So I think the pandemic kind of threw off patients getting this treatment on a wider scale. But I think now that we’re past that, more clinics are popping up. And providers and patients are both seeing beneficial results.

Another recent development is, initially, when it was approved, you had to be taking an oral antidepressant to get the treatment. Now that is not a requirement anymore, so you don’t necessarily have to be taking an oral antidepressant to get eseetamine, which I think is a good thing because a lot of times the reason people are coming to us is because those medications aren’t working or they don’t tolerate them. So it’s kind of like an extra burden for them to have to just take something so they can get a treatment that’s helpful. So I think that’s been helpful too, you have patients who just don’t want to take those meds right now because they’ve had bad experiences and they haven’t worked and now–

Carolyn: They have side effects. And they typically take a lot longer to kick in.

Dr. Battersby: Yes. Yeah, they take longer to kick in. And, I think, generally, the effects are not as drastic. And again, those oral medications do have an impact on the connections between neurons and neuroplasticity, the same things that esketamine effects, but esketamine seems to affect those things more quickly and more potently. And so patients are able to, you can see it, they’re exercising, eating better, getting back involved in different habits or hobbies that they felt were enjoyable for them, getting back to work. So all these really important things that really create stability in people’s lives, I think this treatment more so than other treatments is allowing that to happen.

Carolyn: That’s great.

Chris: Dr. Caleb Battersby is UConn Health’s director of interventional psychiatry. Now, you also, I would imagine, offer other treatments other than the ones we’ve talked about today. So there would be occasion for someone to just call your office and be like, “Hey, can you see me?” I would imagine.

Dr. Battersby: Yes. I see patients, besides esketamine and ECT, I do manage patients, just kind of regular outpatient care, medication management.

Chris: OK, so you do need a referral to get the esketamine treatment and the ECT, but there are others that people can just self-refer and get in touch with you.

Dr. Battersby: Correct.

Chris: So the point of that whole thing was, we’ll put how to get in touch with you in the notes of the show, along with the website you mentioned to get more information on esketamine, the one where we put the ZIP code in, kind of find out what’s around.

Dr. Battersby: Yes.

Yeah.

Chris: So we’ll put all those in the notes for the show, for those listening to look at that information. That is our time for today. For Dr. Battersby and Carolyn Pennington. I’m Chris DeFrancesco. Now thank you to Ryan Burnat for your studio support today.

And thank you for listening to the UConn Health Pulse. Be sure to subscribe so you can catch us next time, and please share with a friend.