23.2 Drug Advertising: the VIOXX Tragedy with Michael Shuman, PharmD

[00:00:00] But when your own internal study shows that rofococcib is causing a four to five times increased risk of a heart attack and stroke when compared to the standard of care at the time, naproxen, that's a major issue.

[00:00:18] It would be one thing if you cut your losses at that point and said, yeah, we don't want to put this drug out because it's actually causing worse side effects,

[00:00:27] even though it's working the way we intended with less bleeding, well, maybe we shifted that paradigm way too much in the other direction.

[00:00:35] And so now people are throwing clots everywhere.

[00:00:38] The end all be all, the official number was somewhere around 50,000 deaths and 150,000 heart attacks and strokes.

[00:00:50] Somebody get this guy some help!

[00:01:04] Or, put more simply...

[00:01:07] If you need help like this guy, call your own doctor.

[00:01:09] So, the first specific example that we want to review again with the viewers and listeners is about a drug called VIOX.

[00:01:18] So, rofococcib or VIOXX was a drug that got approval in, was it 1999 I think?

[00:01:26] Somewhere around there, yeah.

[00:01:27] Got approval in 1999.

[00:01:29] It is an NSAID or a non-steroidal anti-inflammatory drug similar to something like naproxen or Aleve or ibuprofen or Advil.

[00:01:39] So, the background on VIOXX, it's a drug that was created and marketed by Merck.

[00:01:46] And they created it because NSAIDs typically have elevated bleeding risk, especially in the stomach and the GI tract.

[00:01:57] And most NSAIDs, they act on a system called the COX system.

[00:02:02] There are two major branches of the COX enzyme, COX enzyme 1 and 2.

[00:02:08] I'll let you take over and tell me a little bit more about 1 and 2 and why they did this.

[00:02:12] Yeah, there's a lot of these different families.

[00:02:14] Cycle oxygenase 1 and 2.

[00:02:16] And so, with blocking COX-1, you get a thinning of some of the prostaglandins and any prostacyclins.

[00:02:22] And so, what you get there is a thinning of the mucosa.

[00:02:25] And you combine that with some antiplatelet effects and you get the idea that these are GI irritants.

[00:02:30] And you get the risk of GI bleeding.

[00:02:32] What if you can avoid that by going to something that is just COX-2 selected?

[00:02:37] And so, the idea that it maintains the integrity of the stomach and the mucosa there,

[00:02:42] wouldn't that be a medication now that we don't have to worry about as much of those side effects?

[00:02:47] It sounds great, Chubin.

[00:02:48] It does.

[00:02:49] And again, that's the idea initially is why not purify it?

[00:02:52] Like with other things, we know that there's a couple of different enzymes.

[00:02:55] And we've been doing this kind of shotgun approach.

[00:02:58] What if instead of using a hammer, we have a very refined pick?

[00:03:03] And so, instead of slamming something down, we can just get to just what we want.

[00:03:07] And so, on paper there, it does make sense.

[00:03:09] You have a theoretical basis for why something might be better.

[00:03:13] But it's got to be backed up by the actual real-life data and seeing people get better without having side effects.

[00:03:21] Yeah, the fancy thing they taught us was they had about in vitro and in vivo correlation.

[00:03:25] That you can do a study and you can isolate some cells and you can say that,

[00:03:28] aha, this blocks this thing but doesn't do that other thing.

[00:03:32] This is exactly the binding affinity we want to make the perfect drug.

[00:03:35] But then what happens when you put it into an actual animal and then to an actual human being?

[00:03:41] Does it get where it should?

[00:03:43] And when it's in a whole body with much more different types of cells, what does it do there?

[00:03:48] It almost seems like with Vioxx, you know, you take out the COX-1 blocking effect,

[00:03:54] which takes out the bleeding risk.

[00:03:57] But maybe we underestimated the fact that COX-2 blocking maybe causes a prothrombotic effect

[00:04:06] or an elevated risk of clotting, which is exactly what we saw with Merck's study that they did.

[00:04:15] And it's called the Vigor study, the Vioxx gastrointestinal outcomes and research study or something like that.

[00:04:24] Sounds right.

[00:04:24] And so, yes, it did show a decreased bleeding risk with Vioxx that was significant.

[00:04:30] Less stomach bleeding, less blood in the stool, less of that risk.

[00:04:35] But in terms of acute and immediate risk, our GI tracts are bleeding pretty much all the time.

[00:04:41] Very, very minute amounts.

[00:04:43] Our GI cells are turning over on an everyday basis.

[00:04:47] And so there are these little bleeds that happen periodically.

[00:04:51] And the risk of bleeding is definitely something serious that we want to address.

[00:04:55] But when you have your own internal study that then shows that rofococcib is causing a four to five times increased risk

[00:05:07] or more likely risk of a heart attack and stroke when compared to the standard of care at the time, naproxen,

[00:05:15] that's a major issue.

[00:05:17] Now, it would be one thing if you, you know, cut your losses at that point and said,

[00:05:23] yeah, we don't want to put this drug out because it's actually causing worse side effects,

[00:05:27] even though it's working the way we intended with less bleeding.

[00:05:31] Well, maybe we shifted that paradigm way too much in the other direction.

[00:05:36] And so now people are throwing clots everywhere.

[00:05:38] The end all be all, the official number was somewhere around 50,000 deaths and 150,000 heart attacks and strokes.

[00:05:48] There's a lot of people who estimate that number is actually a lot bigger.

[00:05:52] And this study, this bigger study, you know, this is coming out against the context, you know,

[00:05:56] this is you're talking years into a development process.

[00:05:58] So, you know, lots of money, lots of time and effort is being poured in by the company beforehand

[00:06:04] to go through the different studies, again, to evaluate, find a molecule, to see what it does.

[00:06:09] And so there's a little bit of this kind of the sunk cost fallacy that's probably playing in here.

[00:06:14] But now you're at a crossroads, as you said.

[00:06:15] We've got this internal data that's concerning.

[00:06:18] We've put a lot into this so far.

[00:06:19] So what happens?

[00:06:21] Yeah.

[00:06:21] And again, just to remind you, this is two years after that loophole opened up for direct-to-consumer advertising.

[00:06:28] In 1999, Merck spent $160 million on advertising for Vioxx direct-to-consumers.

[00:06:38] 2000, this study comes out.

[00:06:40] Part of the, you know, stage four clinical trials is to continue to study your drug.

[00:06:45] And we have kind of gotten into a system where we forgot that stage four clinical trials exist.

[00:06:51] But at the time, this comes out and what does Merck do?

[00:06:55] They double down.

[00:06:56] They actually try to make the claim that it's not that Vioxx offers more risk to the heart or to the brain or to clotting.

[00:07:08] They say, no, naproxen is actually cardioprotective, which is moving the goalposts, as David Healy, I think, said to me.

[00:07:16] So in, I believe it was early 2001, the FDA Arthritis Drugs Advisory Committee met to discuss this risk.

[00:07:27] And they communicate to Merck that they need to put a plan in place to better educate and try to explain why they should, you know, continue this drug and not ban it with all the elevated major, major risks.

[00:07:43] Well, one day later, Merck puts out what it calls the cardiovascular card, sends it to 3000 plus of their sales representatives.

[00:07:54] And they claim that, again, naproxen is cardioprotective.

[00:07:59] And actually, in terms of overall mortality, Vioxx has one eighth the overall mortality of other NSAIDs.

[00:08:08] Now, how did they get there?

[00:08:10] Well, they pooled a bunch of previous data on NSAIDs.

[00:08:14] And for Vioxx, they used low doses and studies that had a short amount of time that they were studied.

[00:08:22] And if I can just take a moment, this is, yeah, pet peeve of mine is pooling data.

[00:08:26] If you can't get statistical significance in one study, you can create a bunch of small studies and then mash them together.

[00:08:33] And if something looks ugly on its own, you mash it in with a bunch of other things, just like, you know, you make a bad sample of something, you just dilute it down.

[00:08:40] And the idea that you can either make things come out that wouldn't normally or the bad things kind of go away once you dilute it out there and kind of fuzzy it up with a bunch of other data.

[00:08:48] And that's exactly one of the kind of the tricks it can be to working with studies.

[00:08:52] Yeah.

[00:08:53] And so they essentially cherry pick the data and that could go both ways.

[00:08:56] Like a company could intentionally do a review on lithium because, you know, companies are making a bunch of money off of lithium.

[00:09:06] But what it does do is it prevents people from being on more lucrative drugs.

[00:09:11] And actually, lithium prevents them from being on as many drugs as they would be otherwise.

[00:09:17] They can show a negative response by pooling together a bunch of negative studies or they can take a bunch of small 10-person, 15-person studies that show a benefit that are not very rigorously controlled in terms of randomization and creating a true randomized controlled trial.

[00:09:38] And then they can have a paper that says that Vioxx has one-eighth the mortality, but it's not an even playing field.

[00:09:46] It is not looking at the same effective dose of Vioxx versus ibuprofen versus Aleve in 10,000 patients and following them over time, which is the way it should be done.

[00:09:59] Yeah, and that's just, again, just without getting into a whole other stuff, that's one of the common ones where if you want to pick on another drug is you pick on them and you choose the lowest possible dose.

[00:10:08] So if you're a new antipsychotic, you say, all right, well, maybe we're not the best, but we're certainly better than resperidone 0.5 milligrams.

[00:10:14] Yeah, yeah.

[00:10:14] Have you seen the latest actual well-done independently done meta-analyses on lithium and weight gain?

[00:10:22] I have not.

[00:10:24] Oh, it does not cause weight gain.

[00:10:27] There's only one mood stabilizer that is associated with less weight gain that is weight neutral or even promotes weight loss, and that's Lamictal.

[00:10:35] That's what I was assuming you were going to say.

[00:10:36] There are multiple big studies done that actually show that lithium is either weight neutral or a couple of them, that it promotes weight loss.

[00:10:45] It's funny because you'll see in a lot of places that lithium has – it's not as bad as divalprolix, but it still is a weight-positive medicine.

[00:10:51] It is not.

[00:10:52] Don't believe it.

[00:10:53] Just don't believe it.

[00:10:54] There we have.

[00:10:55] And that's – yeah, and you look at what it does.

[00:10:58] I mean it doesn't mechanistically make a lot of sense.

[00:11:01] It will be weight-promoting given something serotonergic.

[00:11:04] But anyway –

[00:11:05] Yeah.

[00:11:06] We'll come back to that at another time.

[00:11:09] With Vioxx, it gets even worse.

[00:11:13] Around this time, there's a cardiologist at, I believe, the Cleveland Clinic.

[00:11:17] His name is Eric Topol.

[00:11:19] And he sends, I think, a comment on the Vigor study or he starts sounding the alarm and trying to talk to Merck's representative saying this is really dangerous.

[00:11:29] People are dying from this.

[00:11:31] And I'm a cardiologist.

[00:11:32] I've never, ever heard that naproxen is cardioprotective.

[00:11:36] But he basically gets bullied.

[00:11:40] Merck, Alice Rison or Riesen, sends a warning that if he tries to publish his commentary or his response in JAMA, one of the major medical journals in the world, that he's going to be met with criticism.

[00:11:57] And essentially you've got kind of the mob idea.

[00:11:59] It's going to be a shame if your entire well-being were to say, you know, go kaput with this or I can't do a good mobster accent.

[00:12:06] But the same idea, it sounds like.

[00:12:08] And I tried to not go too far down the rabbit hole, but of course I reached out to Eric Topol about a year ago to see if he would have any interest in talking about this experience and getting his firsthand account.

[00:12:23] And he emailed me back and it was really disheartening.

[00:12:27] He just said that was a very, very difficult time period for me and my family.

[00:12:33] And I just can't go back and revisit that.

[00:12:35] That's like John Grisham book stuff right there.

[00:12:38] I mean, that's wild.

[00:12:39] I know it does.

[00:12:40] It makes me wonder what was he told if he kept sounding that alarm, like what was going to happen?

[00:12:47] You're right.

[00:12:47] It does sound very mobbish.

[00:12:49] So it actually gets even worse than that though.

[00:12:52] So, you know, this drug was eventually recalled, but it came out down the line that the Vigor study, the initial study that Merck designed,

[00:13:01] was designed specifically to exclude patients that are at high risk for having a heart attack or throwing a clot.

[00:13:10] Which is something, again, I know we're going to talk about later.

[00:13:13] There's cherry picking on one end, but there's the idea that you can literally exclude all the problems.

[00:13:18] You know, we're going to have a population made up of everyone we don't want to have in it.

[00:13:22] Whether we want to show that the drug works or, in this case, doesn't do a thing.

[00:13:26] Say, all right, all the people that could have a bad thing we're going to exclude.

[00:13:30] So only the perfect ones.

[00:13:32] And then we try to say that this is representative of a larger sample.

[00:13:35] And that goes back to why, you know, students are taught about things like journal clubs and looking at the inclusion criteria because of so much.

[00:13:41] You have to, does this apply to my patient population?

[00:13:43] I'm sure if you were a cardiologist, you'd say, there's no freaking way that this applies to my patient population because none of my patients are even in the study.

[00:13:49] Yeah, and to me, it is even more egregious in the fact that they already knew there was at least a theoretical risk before they ever started the Vigor trial.

[00:13:59] I would say they probably had a little bit more data at that point to kind of indicating, okay, this might be a problem for us.

[00:14:06] They try to design the study so that they don't have an increased risk of heart attack.

[00:14:12] And then they still have a four to five times increased risk compared to naproxen, which is pretty damn significant.

[00:14:21] It's also kind of funny because a few years ago, I know there was a study that implied that naproxen was better than some of the other NSAIDs.

[00:14:28] And I believe that they actually asked if they could put that on the label.

[00:14:31] And the FDA is like, no.

[00:14:32] It's kind of ironic then.

[00:14:34] Even the FDA is like, no, no, you can't put that on your labeling.

[00:14:36] But even obviously Vioxx was trying to use that too.

[00:14:38] Yeah.

[00:14:39] And, and to, you know, I just got to point out, like Michael and I are trying to find humor in this.

[00:14:47] It's a very serious subject.

[00:14:49] There are tens of thousands, some people say hundreds of thousands of people who are dead prematurely because of this drug.

[00:14:57] But this is something that we see every day and it can be so disheartening.

[00:15:04] It can lead you to be so downtrodden on what you do and in the system that you work in.

[00:15:10] So it's some of that kind of gallows humor that we got to use to be able to keep pushing on and keep trying to do what we do in order to educate and treat people the way that they should be treated in the medical system.

[00:15:24] And again, for me, this is also one of those reasons why there is a hesitancy about when a new drug comes out is, you know, somebody sees an ad and says, I'm going to be on this drug.

[00:15:33] Okay.

[00:15:33] Well, just let them be on it.

[00:15:34] But there is that concern because until you, you know, fully know, you know, to, to really do that full review and, you know, there's drugs coming out without setting on too much of a tangent coming out now.

[00:15:44] And the FDA will approve it based upon studies, but then you can't act.

[00:15:47] The studies aren't even out yet.

[00:15:48] You don't even have the studies to review prior to the drug getting approved.

[00:15:53] You kind of have to wait.

[00:15:53] The FDA says this drug is approved based upon a couple of really good studies.

[00:15:57] You wait several months for the FDA's website to include those studies and the review.

[00:16:01] And by then, again, it might even already be on the shelves.

[00:16:04] And then you can go back and look at the data.

[00:16:06] But still, it's what is it like in that post-marketing phase?

[00:16:09] And that can be where some of the really important stuff comes out.

[00:16:12] So early adopters, you do have to be aware of that, that sometimes not everything has come out as far as what it looks like in a larger population.

[00:16:19] Yeah.

[00:16:20] And, you know, my patients from a 30,000-foot viewpoint, I may be having, you know, a patient miss out on a breakthrough new drug.

[00:16:30] Because if I don't have the data and I'm supposed to just trust the company that is making and profiting from the drug, I just can't.

[00:16:39] I have too much skepticism to be able to trust that.

[00:16:43] But the other thing that I'll do for my patients is there will be 99 others that are not harmed by that new drug.

[00:16:50] Because most of these new drugs are not staying over time.

[00:16:56] Most of these drugs, we look back 15 or 20 years later and we say, well, gosh, that one really didn't work, did it?

[00:17:04] Same thing with this one.

[00:17:06] Came out, FDA approved in 1999.

[00:17:08] By 2004, Vioxx was recalled.

[00:17:12] And that was too late for anywhere between 50, 150,000 people who died and 150,000 to 500,000 people who had a heart attack or stroke.

[00:17:23] Vioxx was recalled after five years on the market.

[00:17:26] And, you know, they end up paying almost $5 billion in settlement money for egregiously misrepresenting the data that they were already aware of.

[00:17:37] But they made $1.2 billion in 2003 alone on Vioxx of their $6.6 billion.

[00:17:44] It's another situation where, and we see these more and more often since 1997, where drugs come out.

[00:17:53] And when you are able to advertise those to everybody in the general public, there are going to be so many people who are very hopeful and they're relying on that hope or the promise of a new drug.

[00:18:08] And they're going to be the ones that fall victim to this if they don't have a skeptical, critically thinking provider at their disposal.

[00:18:19] Celebrex stayed on the market only because it sucked at being cox-toe selective.

[00:18:23] There were the warnings about it, but it turns out it skirted by because it really wasn't – it really isn't even cox-toe selective was what I was told.

[00:18:30] It survived because they lied.

[00:18:31] So, you know, Vioxxycontin should have been two huge warning signs.

[00:18:38] I mean, we're still seeing the Oxycontin fallout to this day with the most people in documented human history being addicted to substances.

[00:18:49] But Vioxx is something that, again, you're not talking about a really rare drug that is not going to be used very often.

[00:18:58] Everybody takes NSAIDs, not ever being a little bit hyperbolic there, but NSAIDs are a huge seller in terms of overall milligrams and number of prescriptions or over-the-counter drugs given out.

[00:19:11] I mean, yeah, people with pain, people with headaches.

[00:19:14] I mean, these are ubiquitous in our lives.

[00:19:16] And so we have a medication class that has classically been regarded as this treats it, this treats pain, it's anti-inflammatory.

[00:19:24] And so, yeah, anything in that system, it's going to be a big user.

[00:19:28] It almost seems like we are in this U-curve of – maybe the opposite of a U-curve – of regulatory oversight.

[00:19:37] Like in the 1800s and 1900s, in that Wild West, there is no regulatory oversight, and we get more and more and more regulations.

[00:19:46] And now there's all these stated regulations, but the enforcement is not there.

[00:19:51] Yeah, I mean, everything is a pendulum-switching reactionary.

[00:19:54] So there's going to be a lag time between an event happening.

[00:19:57] You mentioned that with the sulfanilamide and then you had thalidomide was a justification.

[00:20:01] The FDA is slow, but it's good.

[00:20:03] Clozapine coming out and the FDA being slower to approve than the European countries.

[00:20:07] That was a good thing.

[00:20:09] And then you flip the other way, and it was AZT and the treatments for antiretrovirals were slow.

[00:20:15] Now we need to put –

[00:20:16] For HIV and AIDS.

[00:20:16] Yes, and so we need to push the other way.

[00:20:18] And so, yeah, everything is a pendulum swinging back and forth to a new normal, I guess.

[00:20:24] Yeah.

[00:20:24] Well, I don't know what this normal is that we have now, but it seems like we are allowing snake oil salesmen to take over again.

[00:20:32] And having marketing departments tell people like you and I what is effective and what is safe.

[00:20:38] It's a scary time that we're living in.

[00:20:40] And I do want to point out, I mean, this is not every pharmaceutical company.

[00:20:45] It's not Big Pharma is bad.

[00:20:46] It's like we've been saying.

[00:20:48] Big Pharma's job is to make medications.

[00:20:51] We're one of the most innovative drug makers in the world.

[00:20:54] We are the most innovative healthcare system in the world.

[00:20:58] But for me as somebody that is managing hundreds of people, it can lead to really bad outcomes in individuals.

[00:21:09] Maybe in the long term we have a few more drugs that are brand new and state of the art, but most of those drugs are going to end up failing in the long term.

[00:21:20] I'm not going to use those in my patients.

[00:21:23] Again, it's not the pharmaceutical companies.

[00:21:26] They're not all bad, but there's got to be systematic change.

[00:21:30] We've got to have more regulatory oversight.

[00:21:33] I'm not sure how deep it goes, but I do know that it's not shallow.

[00:21:39] We've got way too many specific examples of how this system has been manipulated or taken advantage of for people to say that it's shallow.

[00:21:49] And that's one of the things that bothers me most talking to other psychiatrists or clinicians that say, oh, no, it's really not that bad.

[00:21:58] And there's a balance.

[00:21:59] Like sometimes I come to it with so much cynicism that I hear new drugs like what are they lying?

[00:22:03] But the idea is to say, okay, have that one eye open that I'm going to realize some of these things for what they are is these trials are just sales ads but in a nice paper in a pub peer review journal.

[00:22:17] And if you see it that way and say, okay, I still need to critically evaluate the results.

[00:22:23] And then like you said, determine does this seem appropriate for my patient?

[00:22:28] And then that's what the duty for you is to make sure then that it correlates to the individual sitting in front of you.

[00:22:34] So I wanted to take just a minute to point out that the New England Journal of Medicine also may be complicit in this whole Vioxx catastrophe controversy.

[00:22:45] This article by the Journal of the Royal Society of Medicine outlines how the New England Journal of Medicine knew about these risks with Vioxx but neglected to warn the public about them, which is their job as a medical journal.

[00:23:02] This article warns that many of these major medical journals, as Michael Schumann points out, are simply an extension of the marketing arm of pharmaceutical companies and that the full data of trials should be published, not in medical journals where an incomplete story is advanced, but on the web for any scientific researcher to be able to evaluate independently.

[00:23:28] One thing you'll never see is you will never see a direct-to-consumer ad for lithium or for any other orphan drug that is not promoted by a pharmaceutical company.

[00:23:37] But it's not because it's not effective.

[00:23:40] It's because nobody is willing to pay, you know, millions of dollars to run a national TV ad on a drug that costs the patient $10 for a six-month supply.

[00:23:51] Yeah.

[00:23:51] I mean, I was just thinking to riff on a movie line.

[00:23:54] It was, you know, the oceans rise, cities fall, and lithium is still available.

[00:23:57] I mean, that's the thing.

[00:23:58] And I had a patient the other day who was asked.

[00:24:00] He's like, lithium is so amazing.

[00:24:01] He's like, I want to come out with a form of a transdermal.

[00:24:04] And I told him, as I said, you know, it's great ideas, but, you know, yeah, no one's putting money into novel lithium approaches because it's available.

[00:24:13] It's generic.

[00:24:14] It's literally in the dirt.

[00:24:16] You know, they're mining it all over the world.

[00:24:18] So Riff El-Malik educated me on this, and he said that you can patent a lithium product.

[00:24:24] It just has to be in a different form.

[00:24:28] Okay.

[00:24:28] And that's where that electrolyte, something like that would be...

[00:24:32] Have you seen, I think it's Liprocin or something like that.

[00:24:36] It's a new lithium product that is better at getting into the brain, and you don't have to take as high of a dosage of it.

[00:24:45] You have my attention.

[00:24:46] It has my attention, too.

[00:24:47] I also worry, you know, lithium is toxic in the brain at too high of a dosage.

[00:24:52] And that goes back to the problem, though, is where are we getting the sample from?

[00:24:55] Because it ain't your brain.

[00:24:56] We're not putting a...

[00:24:56] I don't love...

[00:24:57] I would love if we could put a dipstick in somebody's brain and pull it out.

[00:25:00] You're like, well...

[00:25:00] Exactly.

[00:25:01] You're a little bit low on lithium.

[00:25:03] Let's top you off a little bit and put a funnel down in there.

[00:25:05] It's not...

[00:25:06] I mean, this is probably going to be cut out of this because it's not really relevant, but we rely on a lithium blood marker, right?

[00:25:13] And how much is in the bloodstream at a specific time after you take your lithium.

[00:25:17] Mm-hmm.

[00:25:17] That gives you this nonspecific, indirect measure of how much lithium is actually acting at the site that we want it to act.

[00:25:26] I'm doing my slides on it right now.

[00:25:27] Which is in the brain.

[00:25:28] Correct.

[00:25:28] You are making an assumption that a homeostasis, an equilibrium is reached between the compartment in the brain and the compartment on the other side.

[00:25:38] So everybody has a blood-brain barrier because we don't want all the stuff running through our arteries and veins.

[00:25:44] We don't want it to be able to get into the brain super easily, right?

[00:25:49] And getting into the brain would only be coming from the arteries.

[00:25:52] So ignore the veins comment.

[00:25:53] Right.

[00:25:54] But at the same time, not everybody's blood-brain barrier is the same level of porous as the next person.

[00:26:03] And there are a lot of different factors for that.

[00:26:06] You probably know them a little bit better than I do.

[00:26:08] I know that we're taught as you get older, your blood-brain barrier opens up.

[00:26:12] Yeah.

[00:26:12] But it's not like you turn 65 and you get your Social Security and boom, your blood-brain barrier is two times more porous.

[00:26:18] Everything is a gradient.

[00:26:20] It's going to be a gradual move towards that.

[00:26:22] And so we're still making assumptions, though, based upon your renal function and based upon what's in your bloodstream and saying,

[00:26:31] aha, that means that the same amount proportionally should be in your brain.

[00:26:35] Right.

[00:26:36] Right.

[00:26:36] So anyway, that's why folks like Nasir Gami clinically recommend to titrate lithium to efficacy.

[00:26:44] You do not rely on just some arbitrary blood number.

[00:26:47] You know, there's risks in terms of the condition and underdosing it.

[00:26:51] But to me, there's far greater risks in overdosing.

[00:26:55] And if I can get you well on 150 or 300, then we're going to try to do that.

[00:27:01] Or if I need to start you on 600 or 900 and then gradually bring you down, if you're coming to me with a really very, very suicidal or have a plan or you're even inpatient and actively wanting to harm yourself,

[00:27:15] maybe we kind of load it on a higher dose on the front end and then gradually bring it down to see, you know, where it is effective at the lowest dose.

[00:27:23] Yeah, the idea that in a manic episode, all systems are go and everything's getting processed faster.

[00:27:28] And so as you kind of come down, that maintenance dose, we can ride a little bit of a lower level.

[00:27:34] And maybe that's better for the kidneys, too.

[00:27:36] There's some data saying if anything, it's certainly not going to hurt.

[00:27:39] It may actually be a way to regenerate some of the cells in the kidneys by just being a little gentler with a lithium dose.

[00:27:46] Yeah, I know that I've seen animal studies of rats being induced to have an acute kidney injury and then using, keyword here, low doses of lithium that actually protects those cells from dying.

[00:28:00] So and we know lithium has that effect.

[00:28:02] I mean, it's a pretty darn cool molecule.

[00:28:05] Absolutely.

[00:28:06] But, you know, you look up lithium on Google, the first one of the first things you're going to see is how it's going to kill your kidneys guaranteed.

[00:28:12] I got a paper right now.

[00:28:14] My nephrologist said I could never do lithium.

[00:28:18] Oh, yeah.

[00:28:18] I had to give a patient who's the nephrologist.

[00:28:21] I had to give him a bunch of papers and just say, but I promise you this low dose is not going to be dangerous or damaging for you.

[00:28:29] And you've got all these bipolar family history risk factors.

[00:28:34] You've never been manic, but you've been depressed.

[00:28:36] And so let's get this started now.

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