Vitality Unleashed: The Functional Medicine Podcast

Shots of Hope: Ketamine Under the Skin, Not In Your Veins

• Dr. Kumar from LifeWellMD.com • Season 1 • Episode 101

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Depression can feel like an endless battle, especially when treatments fail one after another. For those with treatment-resistant depression (TRD), that struggle becomes even more profound – affecting approximately one-third of people with major depressive disorder and creating a desperate need for new approaches.

The groundbreaking K-Day study brings fresh hope through an innovative approach: subcutaneous ketamine injections. While ketamine's potential for depression treatment isn't new, this research tackles a crucial practical challenge – finding an administration method that balances effectiveness with accessibility. Unlike complex IV setups or sometimes inconsistent nasal sprays, these under-the-skin injections represent a middle path that could dramatically expand treatment access.

What makes this study particularly compelling is how researchers adapted when initial results disappointed. By shifting from a fixed dose to a flexible, personalized approach that accounted for ketamine's lower absorption through subcutaneous administration, they achieved remarkable outcomes. The flexible-dosing group saw a 19.6% remission rate compared to just 2% in controls – particularly impressive in a population where nearly a quarter had even failed electroconvulsive therapy. The safety profile proved reassuring too, with expected short-term effects like dissociation and blood pressure changes consistently resolving within two hours, and no evidence of cognitive impairment.

While the benefits diminished somewhat after treatment stopped, suggesting ongoing treatment might be necessary for lasting relief, the research opens exciting possibilities. For TRD patients who've exhausted conventional options, subcutaneous ketamine could provide a practical pathway to relief without requiring complex clinical setups. Have you or someone you know struggled with depression that just won't respond to standard treatments? This research suggests better options might be on the horizon. Follow us for more breakthrough mental health developments that could transform treatment for those who need it most.

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Speaker 1:

Imagine, you know, living with depression, trying one treatment then another and nothing, just no relief. It's tough and for about a third of people with major depression, well, the standard stuff it just doesn't work. That's what we call treatment-resistant depression, or TRD. It's a profound, often really despair-inducing challenge. But what if there was some new hope, like a rapid-acting that's not just effective but maybe more accessible, more practical? That's exactly the potential we're going to dive into today, and you might have heard about ketamine, perhaps IV infusions or those intranasal sprays but our focus it's on a new and, I think, incredibly practical way to administer it Subcutaneous injections just under the skin. Yeah, so our deep dive today. It's based on this really significant study, the KA study. It was a large scale phase three clinical trial and it looks specifically at the efficacy and safety of repeated subcutaneous ketamine injections for TRD. There's quite a lot here, honestly, that could fundamentally change how we approach treating depression. It could offer a whole new pathway for many people.

Speaker 2:

It's fascinating, isn't it? Because this study, it really tries to tackle some big gaps in what we already know. It offers a practical, potentially game-changing option for those who just struggle to find anything that works.

Speaker 1:

Okay, so let's kick things off by just sort of reiterating the scale of this challenge TRD. When we say treatment-resistant depression, we really mean someone hasn't responded to at least two proper tries of different antidepressant medications. And this isn't just like a clinical label, it's a huge personal struggle. It affects so many lives globally. I mean, major depressive disorder is actually the second leading cause of disability worldwide.

Speaker 2:

Yes, absolutely, and that really underscores the urgent need for new effective treatments that go beyond our traditional options. Now we know intravenous racemic ketamine has shown real promise, right, and there's intranasal esketamine. That's a specific part of the ketamine molecule which has regulatory approval. But finding new feasible ways to give racemic ketamine that's the generic, often lower cost form that's really crucial Because, let's face it, iv infusions can be complex, it can be costly, and the intranasal sprays sometimes the absorption can be a bit erratic. So this study was really trying to get past some of those real world hurdles.

Speaker 1:

Right, so enter the K-Day study. This sounds like a really solid trial design Large, multi-center, phase three, double blind, randomized-controlled, ran across Australia and New Zealand. And, crucially, you mentioned the active-control midazolam. Why was that important?

Speaker 2:

Yeah, using midazolam, which is a sedative, instead of just say saline. It's about blinding. It makes it harder for participants and even the researchers interacting with them to guess who's getting the real ketamine and who's getting the control. Ketamine has noticeable short-term effects, so using something like midazolam helps maintain that blind, making the result more trustworthy.

Speaker 1:

Okay, got it. So how did the study actually run?

Speaker 2:

Well, it started with two groups or cohorts. Cohort one was a fixed dose group that got ketamine at 0.5 milligrams per kilogram twice a week for four weeks Pretty standard IV dose level, just given subcutaneously. But here's the interesting part, or maybe the unexpected part this initial fixed dose it didn't show a statistically significant difference in remission rates compared to the midazolam group. Ketamine was at 6.3% remission, midazolam at 8.8%.

Speaker 1:

Wow, okay. So 8.8% for midazolam, that's higher than the ketamine group. That must have been surprising. So essentially that first approach, it didn't seem to be working as expected. That sounds like a bit of a setback. How did they handle that?

Speaker 2:

That's a great question and this is where the study's adaptability really comes into play. After those first 51 participants went through a data safety monitoring board, looked at the early data, they basically said hey, based on this lack of efficacy, we recommend revisiting the dosage.

Speaker 1:

So for the next group, cohort two, they changed the strategy.

Speaker 2:

OK, so what did they change it to?

Speaker 1:

They made it flexible and response guided. So what did they change it to? They made it flexible and response guided. This meant they could start at 0.5 milligrams per kilogram, but they could increase the dose step by step, up to 0.9 milligrams per kilogram, depending on how the individual is responding.

Speaker 2:

Ah, ok, so personalizing it more. Why the higher potential dose, though? Right, it came down to bioavailability, basically how much of the drug actually gets into your system and is active. It turns out that when you inject ketamine under the skin, subcutaneously, less of it gets absorbed compared to putting it directly into a vein via IV. The bioavailability is about 0.66 or 66%. So the thinking was to get the equivalent effect of that 0.5 milgari milagidos, which we know works. You actually need a slightly higher subcutaneous dose, maybe around 0.75 mG, or even up towards that 0.9 mG of kilograms in some cases. This is a really critical adjustment learning and adapting as the trial went on.

Speaker 1:

And what a difference that made. This is where it gets really interesting, isn't it? In cohort two, that flexible dose group, the results were just well dramatic. You had a 19.6% remission rate for ketamine. Compare that to just 2.0% for midazolam Two percent.

Speaker 2:

Exactly A huge difference.

Speaker 1:

And that translates to a number needed to treat an NNT of just six. That sounds incredibly effective, especially for TRD.

Speaker 2:

It is remarkably effective. An NNT of six in this population is considered very strong. And it wasn't just remission. Those benefits carried over to other key measures too, things like response rates defined as a 50% or greater improvement on the MADRS score that's the standard depression scale they used and also just the overall average reduction in amniotic schools. All significantly better for ketamine in that flexible dose group.

Speaker 1:

And this was in a population that was really treatment resistant right.

Speaker 2:

It's highly treatment resistant. You mentioned it earlier about 24%. Nearly a quarter of them had even failed ECT electroconvulsive therapy which is often seen as a sort of last resort. So achieving these results in that context is particularly impressive.

Speaker 1:

Yeah, it really makes you think about those individuals. I mean failing multiple meds, maybe even ECT. For them, this must feel like a potential lifeline. So, boiling it down, what does this really mean for someone living with TRD right now?

Speaker 2:

Fundamentally it suggests that if you get the dose right using that flexible titrated approach, subcutaneous racemic ketamine can offer really quite large benefits, both statistically significant and clinically meaningful. For a good portion of people with TRD this could be a very viable option and interestingly, there were some signals, maybe hints, that it might be even more effective for people with higher anxiety at the start or those who'd failed more treatments previously, or even those also taking antipsychotic medications. That points towards potential ways we might personalize treatment even more down the line.

Speaker 1:

That's incredibly promising, but you know, the question always comes up Safety. What about side effects, acute effects, longer term?

Speaker 2:

Right Always a critical consideration and the safety findings here were generally quite reassuring. Serious adverse events were rare and, importantly, most weren't even considered related to the ketamine itself and, crucially, no deaths occurred during the study.

Speaker 1:

Okay, that's good. What about those known ketamine effects like dissociation or blood pressure changes?

Speaker 2:

They definitely observe those well-established acute effects, things like feeling lightheaded, maybe a bit disconnected or dissociated, temporary rises in blood pressure. These were more noticeable in cohort two, likely due to the higher potential doses. But and this is key the study reported these effects consistently resolved or went back to normal levels within the two-hour observation period after the injection and, importantly, no one actually needed medical intervention for these acute effects.

Speaker 1:

So manageable within the clinic setting.

Speaker 2:

Exactly. The conclusion was a good acute between session and longer term safety profile. Provided it's given within a careful safety monitoring framework, that monitoring part is crucial, oh and also significant. They found no evidence of cognitive impairment. That's often a concern with ketamine, so that's a positive finding.

Speaker 1:

What about the blinding? You mentioned midazolam help, but did people guess correctly?

Speaker 2:

Yeah, that's a fair point. The study did note that masking wasn't perfect. Participants, especially those feeling better, often correctly guessed they were on ketamine. This is a common challenge with any psychoactive drug study. You know it's hard to fully mask effects that people can feel. But while it's something to consider, it's unlikely that this alone Okay.

Speaker 1:

So the immediate benefits sound strong and the short-term safety seems manageable. But the big question for depression treatment is always does it last? What happened after the four weeks of treatment stopped?

Speaker 2:

That is the million-dollar question, isn't it? Real-world application hinges on this. So they followed up four weeks after the last injection. At that point the difference in remission rates between the ketamine and midazolam groups in cohort two it had reduced. It was 8.0% for ketamine versus 2.1% for midazolam. Statistically that difference wasn't significant anymore.

Speaker 1:

Ah, so the effects faded for some.

Speaker 2:

It seems. So this points to a really important takeaway. The benefits, while significant during treatment, might not be sustained long-term for everyone without ongoing treatment. The study explicitly says ongoing treatment should be considered, and this actually lines up with what we see with other forms like intranasal esketamine, where continued dosing is often needed to maintain the positive effects over longer periods. Okay, that makes sense.

Speaker 2:

So, thinking about clinical practice right now, what's the big takeaway from this study, especially regarding this subcutaneous route? I think the significance is pretty profound really. First, it provides strong phase 3 evidence supporting the safety and efficacy of racemic ketamine. Again, that's the generic, potentially more accessible form. Second, it validates this relatively simple subcutaneous injection method. Compared to setting up IV infusions. This could really increase the potential for clinical use. It's just easier logistically. Third, it really highlights that the flexible dose titration approach used in cohort two seems key to optimizing both how well it works and its safety. It's not one size fits all. And finally, it reinforces that this needs to happen within a proper safety monitoring framework. You still need clinical oversight, but overall it suggests a much more practical path to relief for many people. Melanie.

Speaker 1:

WARRICK it sounds like a really promising development. So, looking ahead now, where does the research go from here? What are the next big crawls?

Speaker 2:

Yeah, the study itself kind of points the way. There's a need for more head-to-head comparisons, like directly comparing racemic ketamine versus S-ketamine or even R-ketamine, and comparing different routes subcutaneous versus IV versus intranasal, for example and, of course the big one, finding better strategies to extend those benefits. How do we reduce relapse rates? How do we best structure ongoing treatment to maintain that hope for people? Those are key areas for future work.

Speaker 1:

Right. So to sort of wrap things up yeah, if we sum, it all up.

Speaker 2:

This deep dive into the KAD study really shows that adequately dosed subcutaneous racemic ketamine looks like a safe and effective option for TRD, at least over a four-week course. The practical nature of the injection is a big plus, potentially overcoming some hurdles associated with IV or intranasal routes. But it's also clear that getting the dose right through careful titration is vital and that maintaining the benefits likely requires some form of ongoing treatment for many.

Speaker 1:

So this research, then, it really does open up a crucial conversation. How could expanding access to treatments like this effective? Practical options like socutaneous ketamine, how could that reshape mental health care? It feels like it moves us a step closer, maybe, to a future where more people living with that really difficult treatment resistant depression can actually find relief, reclaim their lives, perhaps even without needing complex, intensive clinical setups all the time. We really hope this deep dive has given you, our listener, a clearer picture of this evolving field and maybe spark some new curiosity. Until next time, keep exploring, keep learning and definitely keep asking those big questions.