00;00;00;03 - 00;00;20;19 Unknown Imagine a medication that is, you know, proven to work for exactly 21 days, just three weeks, right? And tested on this highly specific group of adults in a really tightly controlled hospital setting. Exactly. And now, I mean, imagine that exact same medication being prescribed to millions of people. And we are talking about healthy children here, too. Oh, yeah. 00;00;20;20 - 00;00;47;10 Unknown Prescribed to take every single day for the rest of their lives. It's wild. Welcome to our deep dive. Today we are unpacking a story that, honestly, it completely flips our understanding of how medicine and science and the law are actually supposed to interact, because we all operate under this collective assumption, right? We assume there's a 1 to 1 correlation between how scientists rigorously test a drug and how your doctor eventually hands it to you. 00;00;47;11 - 00;01;09;09 Unknown Yeah, like if a pill is meant to be taken for decades, you'd think it must have been tested for decades. You would think so. But today's exploration totally dismantles that assumption. We're looking at the deeply documented history of a drug called Devil Pro x sodium, which most people know by its brand name, Deepika. And we have got a massive stack of source material to get through today. 00;01;09;10 - 00;01;43;04 Unknown I mean, we're pulling from FDA regulatory histories, pivotal clinical trials published in Jama Department of Justice settlement documents. Don't forget the personal case study, too. Yes, a truly fascinating case study from a researcher named Brett Kerr, who literally lived this reality for 30 years, which is just an incredible lens to view this through. Totally. So our mission today is to trace how a diagnostic illusion, combined with some incredibly clever legal maneuvering and one wildly successful marketing phrase, just completely reshaped modern psychiatry. 00;01;43;04 - 00;02;11;17 Unknown But I think it's crucial to set the stage for you by clarifying what this deep dive is not right. We're not talking about snake oil here. No, not at all. Deval Pro sodium is a potent biologically active molecule. It has a very real effect on the human brain. It definitely does something. Exactly. What we are exploring is the intersection of pharmacology, diagnostic fads, and these massive systemic loopholes that allow a drugs cultural reputation to just entirely outpace its scientific evidence base. 00;02;11;18 - 00;02;40;18 Unknown It's a story about what happens when the medical field takes a very narrow, highly specific tool, you know, and it decides to just apply it to a massively broad, lifelong problem without any long term evidence. Right. And to understand how this went so wildly off the rails, we really have to travel back to the 1990s. We have to look at the bedrock of why this drug was approved in the first place, because the foundational reality of depth code is incredibly specific, highly specific. 00;02;40;18 - 00;03;02;01 Unknown It was approved by the FDA in 1995, and then an extended release version was approved later in 2005. But the indication like the exact medical scenario the FDA said it could be legally marketed for, was identical. Right? They didn't change the core approval exactly. It was approved exclusively for acute, manic or mixed episodes associated with bipolar disorder in adults. 00;03;02;01 - 00;03;23;22 Unknown And the language there is incredibly important for you to note acute manic episodes in adults. Acute being the keyword, right? The trials that actually secured this approval were measuring an acute intervention in a hospitalized setting. To really grasp the scale of this, we need to look at the actual mechanics of those early pivotal clinical trials. Yeah, let's get into the numbers because they are shocking. 00;03;23;22 - 00;03;48;08 Unknown So in 1991, a researcher named Pope and his colleagues ran a trial. They took hospitalized adults who were experiencing severe mania, and they randomized them to receive either valproate or a placebo. Okay. And how many people are we talking about here? The entire enrollment for that driver was 36 people. Wait, just 3636 people total. And the duration of the observation was exactly 21 days. 00;03;48;08 - 00;04;09;07 Unknown I just need to pause on that for a second. 36 people for three weeks. I mean, that is literally the size of a single high school classroom. It is an incredibly small sample. I mean, it's tiny, but they did build upon it. Okay, slightly bigger trial then. Yeah. In 1994, Bowdoin and colleagues published the landmark trial in Jama that truly cemented the drug's approval. 00;04;09;07 - 00;04;34;20 Unknown The big one, right? They randomized 179 hospitalized, acutely manic adults. They split them into three groups one taking devel pro X, one taking lithium and one taking a placebo. And how long was this one? Again? The duration of this highly controlled observation was exactly 21 days. Wow. I found myself doing the math on this while I was going through the sources, and the total numbers are just staggering in how small they are. 00;04;34;21 - 00;04;58;20 Unknown They really are. Because when you aggregate all the patients across every single pivotal registration trial for acute mania that this drug relies on, fewer than 500 patients were ever randomized to double pro X against a placebo. Less than 500 people. Yeah, less than 500 people tested for just three weeks. And that became the foundation for a medication that was prescribed to millions of Americans for decades. 00;04;58;20 - 00;05;17;08 Unknown At a stretch, the discrepancy between the evidence base and the eventual real world application is massive. I mean, it's a chasm. It really is. But, you know, to be fair to the science of those initial three weeks, we absolutely have to acknowledge the efficacy reality, right? Because it wasn't a total failure in the short term. Not at all. 00;05;17;11 - 00;05;46;28 Unknown For that specific acute 21 day window, the molecule did exactly what it was supposed to do. It works. It did. In that 1994 Bowdoin trial, the Devil Pro X Group saw a 50% symptom reduction in 48% of the patients. Okay. Almost half. Yeah. Whereas the placebo group only saw that reduction in 25% of patients. So in the realm of psychiatric interventions for severe mania, that is a highly robust, clinically meaningful signal. 00;05;46;28 - 00;06;06;04 Unknown And the sources actually translate that into a number needed to treat or NNT of about four. Yes, which is a great metric. It's this brilliant little statistical tool. It basically means you only have to treat for acutely manic people with this drug to get one dramatically positive outcome. That wouldn't have happened if they had all just taken a sugar pill. 00;06;06;05 - 00;06;28;21 Unknown And honestly, an NTF four is considered quite strong in psychopharmacology, right? It's not a negligible effect. Exactly. And this efficacy wasn't just some fluke isolated to those early trials either. They confirmed it later, right? Yeah. There was a 2013 Cochrane synthesis. And Cochrane reviews are basically the gold standard for independent pooled data analysis. They strip away all the bias, right? 00;06;28;23 - 00;06;55;05 Unknown They stripped away all the pharmaceutical company framing and they confirmed the effect. They looked at multiple randomized trials encompassing 869 participants. Okay. Bigger pool. Yeah. And they found a 45% response rate for the drug versus a 29% response rate for the placebo. The odds ratio was just above two favoring the drug. So if we think about what acute mania actually is I mean, the brain is racing. 00;06;55;05 - 00;07;20;11 Unknown There's a complete departure from reality, the absolute lack of sleep. It is a full blown neurological crisis. It has devastating. Yeah. So I like to picture this specific drug as a heavy duty industrial fire extinguisher. That's a good way to look at it. Right. Because these clinical trials from the early 90s proved completely and definitively that if your kitchen is actively engulfed in flames, this specific chemical foam is highly effective. 00;07;20;11 - 00;07;46;04 Unknown It will put out the fire in 21 days. That is a perfect framework for it. It is an acute tool for a severe, immediate, highly visible crisis. Exactly. Biologically, the molecule acts as an anticonvulsant. It fundamentally alters the brain's excitability like it slows everything down. Right? It's believed to increase the levels of gamma aminobutyric acid, or Gaba, which acts as the primary inhibitory neurotransmitter in the brain. 00;07;46;04 - 00;08;09;07 Unknown So it's basically the chemical brake pedal, exactly the brake pedal. And at the same time, it is thought to block voltage gated sodium channels, which stops the neurons from firing so rapidly. So your fire extinguisher analogy is biologically sound. It suppresses the neurological inferno. Okay. So it puts out the fire. Yeah. But then the medical field essentially made this massive, totally unsupported leap in logic. 00;08;09;08 - 00;08;32;07 Unknown They really did. They looked at the data and said, wow, this heavy duty fire extinguisher is amazing at putting out active kitchen fires. Therefore, the logical thing to do is to take this chemical foam and spray it all over your living room every single day for 30 years, just to prevent the room from ever getting warm. That is exactly the assumption the entire prescribing culture adopted, which is just crazy. 00;08;32;07 - 00;08;54;15 Unknown When you say it out loud. It is because Devil Pro X suppressed an acute manic episode in a hospital for three weeks. The clinical consensus became that it must also work indefinitely out in the real world to prevent mood episodes from happening in the first place. They just assumed that acute suppression mathematically equals long term prevention. That was the fatal assumption. 00;08;54;15 - 00;09;16;26 Unknown Yeah. Which raises an immediate question about testing. Right. Because of a doctor in 1998 is looking at this incredible three week data. The logical next step is to test what happens on day 22 or day 300. Yeah, right. Someone had to have run a trial to see if spraying the fire extinguisher every day actually stops future fires. Well, the thing is, they did run that trial. 00;09;16;27 - 00;09;39;16 Unknown They did? Yeah. The sponsors funded a maintenance study to test that exact prophylactic hypothesis. And the result were completely ignored by the mainstream prescribing culture. Oh, wow. So this is what the source material refers to as the maintenance gap. Exactly. The maintenance gap. Let's dig into that gap. Because of the contrast between the actual data and the real world, prescribing is just wild to me. 00;09;39;16 - 00;10;02;21 Unknown So this trial was led again by Boden and published in the Archives of General Psychiatry in the year 2000. And this was a 52 week maintenance trial. Okay. A full year of observation. That's a real test, right? They enrolled 372 outpatients who had recently experienced a manic episode, and they randomized them to receive either lithium or a placebo. 00;10;02;21 - 00;10;22;05 Unknown And what were they looking for? The primary endpoint, the singular confirmatory question the trial was designed to answer was whether this drug increased the time before a patient experienced another mood episode. So they wanted to prove the fire prevention theory. If you take this every day for a year, does it stop the mania from coming back? Better than taking a sugar pill. 00;10;22;06 - 00;10;44;25 Unknown Exactly. And the data showed a shocking null the total failure. Total failure on the primary endpoint, the Devil Pro X Group, did not differ significantly from the placebo group, meaning it was no better than nothing, right? It did not prevent the recurrence of mood episodes better than taking nothing at all. I can just imagine the pharmaceutical company scrambling when they saw that data. 00;10;44;26 - 00;11;11;20 Unknown I mean, they must have tried to salvage it somehow, maybe pointing to secondary measures. Well, they absolutely did. The drug did beat the placebo on a few secondary metrics, like fewer patients dropping out of the study prematurely because they felt themselves getting sick again. Okay, so a tiny silver lining, sure. But in rigorous clinical trial methodology, if a drug fails its primary endpoint, you cannot use the secondary endpoints to claim victory, right? 00;11;11;20 - 00;11;33;14 Unknown Because that's moving the goalposts. Exactly. Those secondary metrics become interesting observations, you know, perhaps fodder for future hypotheses, but they are not proof of efficacy. The confirmatory question returned a null result, and it actually gets even worse for the drug's long term profile. About a decade later, when an independent group decided to run their own test. Yes, the balance trial. 00;11;33;18 - 00;11;55;10 Unknown This is a huge win. Tell me about balance. So it was published in The Lancet in 2010, and its importance really cannot be overstated because it was funded by the UK government. So no pharmaceutical money? Absolutely zero. Pharmaceutical money or influence evolved. They tracked patients over 24 months, which is a massive window for a psychiatric trial two whole years. 00;11;55;11 - 00;12;19;10 Unknown Right. And they compared valproate monotherapy, meaning taking only depicted against lithium monotherapy and against a combination of both drugs. So it's a two year independent head to head showdown. And Dip code essentially came in at dead last dead last dead last. Over those 24 months, patients taking only valproate had a 69% relapse rate. Wow. Lithium alone had a 59% relapse rate. 00;12;19;10 - 00;12;38;14 Unknown And the combination therapy had a 54% relapse rate. So almost 70% of the people taking the drug to specifically prevent a relapse ended up relapsing anyway. It was the worst performer of the three arms. That is brutal. It really is. And this complete lack of long term evidence is actually reflected in the regulatory standing of the drug to this very day. 00;12;38;16 - 00;13;04;13 Unknown It's like officially, officially diving pro sodium is not FDA approved for the maintenance or prophylaxis of bipolar disorder. Wait, really? After all this time, even today, if a physician actually reads the fine print on the FDA label, it explicitly states that the safety and effectiveness for long term use in mania, meaning anything beyond three weeks, has not been systematically evaluated in controlled clinical trials. 00;13;04;13 - 00;13;22;04 Unknown So let me get this straight. We have a drug that failed its own one year sponsor trial. It came in dead last in an independent two year trial. Also true. And it carries a literal disclaimer from the FDA saying it hasn't been proven to work past 21 days. Exactly. Yet millions of people were taking it for years at a time. 00;13;22;05 - 00;13;49;00 Unknown I mean, the obvious question here is how? How did an entire medical community convince itself to ignore all this data and prescribe this thing indefinitely? It's a great question, and the answer lies in the incredible power of language. In medicine. Language? What do you mean? It was achieved through this, this semantic triumph, the widespread adoption of a very specific, highly engineered phrase and what phrases that mood stabilizer are. 00;13;49;02 - 00;14;18;18 Unknown Right? Because when you hear the term mood stabilizer, I mean, it sounds incredibly scientific. It does. It sounds like a defined biological mechanism, you know, like beta blocker or selective serotonin reuptake inhibitor. You just assume there is a specific gear in the brain that is literally being stabilized. And that is the brilliance of the illusion. The term mood stabilizer has absolutely zero pharmacological or regulatory definition. 00;14;18;18 - 00;14;38;24 Unknown None. None. It does not exist in the FDA's vocabulary as a recognized mechanism of action. It was entirely an informal category invented by clinical shorthand. It's essentially a marketing term dressed up in a lab coat. That is exactly what it is. I mean, think about it like trying to sell a snow Clough. Right? If you call it an asphalt scraper, people only buy it when it snows. 00;14;38;24 - 00;14;59;02 Unknown But if you invent a new term and call it a weather stabilizer, suddenly people think they need to drive it around in July to prevent thunderstorm. Exactly. That's exactly it. Your analogy captures the psychological shift perfectly, because if you tell a psychiatrist, hey, this is an acute anti manic get convulsions that sedate hyper dopaminergic states for 21 days. 00;14;59;03 - 00;15;24;11 Unknown Well that psychiatrist will use it for 21 days on an inpatient ward. Right. They'll use the tool correctly. But if you call it a mood stabilizer you imply this fundamental symmetry, right. The word stabilizer suggests that if it suppresses the manic high, it must also symmetrically prop up the depressive low. Like it just levels everything out. Yeah, that it holds the entire architecture of the brain in a steady, unmovable state indefinitely. 00;15;24;11 - 00;15;51;10 Unknown So the phrase itself does all the heavy lifting that a clinical maintenance trial never could. Precisely. It bypassed the need for biological evidence by just sounding intuitively correct. Wow. And that clinical law allowed the medication to effortlessly cross the boundary. Right? It went from being a short term emergency room intervention to becoming an everyday, lifelong household staple. And once that boundary was crossed for adults, the threshold for who could receive the drug just plummeted. 00;15;51;11 - 00;16;12;28 Unknown It did. It really opened the floodgates. Which brings us to the 1990s and 2000, where this lack of evidence took a massive and honestly, quite terrifying leap the pediatric era. Yeah, because if prescribing it long term to adults was a stretch, applying this heavy duty chemical fire extinguisher to developing children was an entirely new paradigm, a very dangerous one. 00;16;12;28 - 00;16;33;20 Unknown So let me share a statistic from the source material that is genuinely hard to fathom. Go for it. Between the years 1994 and 2003, in the United States office visits where a youth so a child or a teenager received a diagnosis of bipolar disorder rose by approximately 40 fold 40 fold. That is just a staggering multiplier. It's insane. 00;16;33;20 - 00;17;00;11 Unknown It went from roughly 25 visits per 100,000 population to over 1000 visits per 100,000. But you know, it is vital to clarify the epidemiology behind that number for you, right? We were not witnessing a 40 fold outbreak of a biological disease, right. Kids weren't suddenly mutating. Exactly. Human genetics do not alter themselves that rapidly. What that statistic actually measures is a massive spike in the diagnostic label being applied by clinicians. 00;17;00;11 - 00;17;26;13 Unknown It tracks the popularity of the diagnosis, not the true incidence of the illness. Right. It was a trend. The culture of psychiatry shifted, and suddenly hundreds of thousands of children were walking out of doctors offices with a label that used to be reserved for severely ill adults, and because depicted, was the reigning mood stabilizer for adults at the time, it naturally became the go to prescription for these newly diagnosed kids. 00;17;26;13 - 00;17;52;15 Unknown So the manufacturer, Abbott Laboratories, realized they had this massive new market on their hands. So they finally decided to run a pediatric trial. Right. This is the Wagner 2009 pediatric trial. Let's talk about Wagner. So the goal was to formally test if Divo Pro X actually worked in this massive new demographic of children. They enrolled 150 children and adolescents ranging from 10 to 17 years old, all of whom carried a diagnosis of bipolar disorder. 00;17;52;15 - 00;18;17;15 Unknown And they randomized them to receive either the extended release version of Deal Pro X or a placebo for 28 days. And they were measuring success using the Young Mania Rating Scale. Or why am I right? Correct. The year tracks manic symptoms, so if the fire extinguisher works, the symptoms should drop dramatically on this scale. But the data from the Wagner trial showed a complete and total failure. 00;18;17;17 - 00;18;39;18 Unknown Absolute failure. The drug completely failed to separate from the placebo. Give us the numbers on that. The statistics are striking. The group taking the active anticonvulsants saw their scores dropped by an average of 8.5 points. Okay, the group taking the inactive placebo saw their scores dropped by 8.0 points. Wait, so an 8.5. drop versus an 8.0. drop? Yep. 00;18;39;20 - 00;18;58;16 Unknown In clinical research, a half point difference on a subjective rating scale is indistinguishable from statistical noise. The trial was a definitive null result, but if we just look at this purely biologically, it doesn't seem to make sense. How so? Well, we know the molecule works incredibly well on a 22 year old brain experiencing acute mania in a hospital. 00;18;58;17 - 00;19;20;15 Unknown Right. All right. The fire extinguisher works on active fires. So are we supposed to believe that the basic chemistry of the human brain changes so drastically between age 15 and age 22, that a potent drug just suddenly forgets how to do its job? And that is the exact paradox that doctor Mark Ritter, the FDA medical reviewer assigned to analyze this failed trial, had to solve. 00;19;20;16 - 00;19;42;17 Unknown Oh, this is the part I find fascinating. It is. His analysis of the Wagner 2009 trial is basically a masterclass in reading between the lines of clinical data, because he realized it wasn't the drug's fault. Exactly. He concluded that the trial did not fail because of developmental pharmacology. The drug didn't stop working because teenagers metabolize anticonvulsants differently than adults. 00;19;42;17 - 00;20;10;20 Unknown So what did it fail? The trial failed because of diagnostic chaos. Diagnostic chaos. So the trial tested the wrong kids? Absolutely. If you look at the adults in the 1991 and 1994 trials, they had classic, narrow episodic mania, right? They had distinct periods where they stopped sleeping, they developed grandiose delusions and completely departed from their baseline reality. But Doctor Ritter noted that the children in this 2009 trial represented a mixed phenotype. 00;20;10;22 - 00;20;42;07 Unknown They did not look anything like the adult patients, because the pediatric diagnosis in the 90s and 2000 had drifted so far away from classic episodic mania. Right. These children were diagnosed largely based on chronic non irritability. They were experiencing severe temper outbursts, you know, effective storms and just constant dysregulation. They were continually explosive, not cyclically manic. Exactly. And Doctor Ritter uncovered a massive fatal flaw in the trial design regarding what these kids were actually taking while the study was happening. 00;20;42;08 - 00;21;08;05 Unknown Oh, right. The confounder was a catastrophic confounder. Doctor Ritter found that an astounding 67% of the children enrolled in this pediatric bipolar trial carried a simultaneous comorbid diagnosis of ADHD, attention deficit hyperactivity disorder. Right? And even more alarmingly, 23%. So nearly a quarter of the entire trial population, we're showing active ADHD symptoms at baseline despite taking ongoing stimulant medications. 00;21;08;07 - 00;21;35;29 Unknown I have to stop and emphasize how absurd that is from a scientific testing standpoint, it's completely nonsensical. I mean, you are trying to test a highly sedating, anti-monarchist, anticonvulsant medication, right? Right. The entire goal is to see if it calms down. Hyperactive manic behavior and a quarter of the children in your data pool are actively taking central nervous system stimulants like amphetamines or methylphenidate every single day of the trial. 00;21;35;29 - 00;22;01;12 Unknown It completely invalidates the behavioral measurements. It's like trying to run a rigorous scientific study on the calming effects of camomile tea on a group of teenagers, but right before you hand them the tea, you force feed a quarter of them double shots of espresso. That's hilarious, but sadly very accurate. The chaotic bouncing off the walls energy from the espresso is going to completely drown out whatever mild sedative effect the camomile is having. 00;22;01;12 - 00;22;24;08 Unknown You can't measure the fire extinguisher when someone is actively pouring gasoline on the fire. Your analogy highlights the exact methodological breakdown. I mean, the adult trials in the early 90s were conducted in tightly controlled inpatient environments before the adults were given Double Pro X, all other confounding psychotropic drugs were meticulously washed out of their systems. They started with a clean slate. 00;22;24;09 - 00;22;51;00 Unknown Yes, but the pediatric trial, however, was an outpatient study basically awash in dopaminergic stimulants. You cannot accurately measure the sedative effect of an anticonvulsant on a behavioral rating scale when a significant portion of the cohort is actively stimulated by amphetamines. So Doctor Ritter looks at this mess of a trial and realizes the data is useless because the kids were misdiagnosed and over medicated with stimulants. 00;22;51;00 - 00;23;17;27 Unknown Correct. But he didn't conclude that Deepika was useless for all kids. Did he know his recommendation was highly precise? He did not advise abandoning the molecule entirely. He recommended that the sponsor rerun the trial, but with strict enrollment criteria. Finding the right kids this time, right. He suggested they only enrolled children who met the National Institute of Mental Health defined narrow phenotype, meaning find the rare children who actually exhibit classic episodic, grandiosity driven mania. 00;23;17;28 - 00;23;42;00 Unknown Exactly. Wash them off all stimulants, and test the drug on that specific population. The failure wasn't the drug. The failure was the diagnostic net they cast. Which brings up a really huge point, because if the hundreds of thousands of kids getting swept up in this diagnostic net in the 90s didn't actually have classic bipolar disorder, we're left with a massive public health mystery. 00;23;42;01 - 00;24;06;17 Unknown We really are. What exactly were these chronically irritable, explosive kids suffering from? To solve that mystery, we have to look at how the psychiatric community eventually underwent a massive nozzle correction nozzle. Break that down for us. Sure. Is basically the branch of medical science concerned with the classification of diseases. We need to examine how the researchers finally admitted their air and redrew the diagnostic lines. 00;24;06;17 - 00;24;29;27 Unknown And this effort was spearheaded by two researchers at the National Institute of Mental Health, Ellen Lebon Lift and Melissa Brotman. They looked at this massive 40 fold spike in pediatric bipolar diagnoses and essentially said, something is wrong here. These kids do not fit the biological model of bipolar disorder and life. And left. And Brotman performed a crucial intervention. 00;24;29;27 - 00;24;53;29 Unknown They recognized that the chronically irritable, constantly explosive presentation was a distinct phenomenon. To study it properly, they had to isolate it from the bipolar label. So they created a new category. Yeah, they operationalized a new phenotype, giving it a temporary research name, severe mood dysregulation, or SMD. By giving it a distinct name, they could finally track these specific kids longitudinally. 00;24;54;00 - 00;25;20;10 Unknown Exactly. They could watch them grow up and see what happened to their brains over time. The fundamental question was, do these chronically irritable, explosive children inevitably grow up to become adults with classic bipolar disorder? Because if they do, then prescribing them as kids makes biological sense, right? If it's the same disease just manifesting early. Yeah, but the longitudinal tracking provided a definitive, undeniable answer, and the data revealed a resounding no. 00;25;20;11 - 00;25;51;27 Unknown They didn't grow up to be bipolar. Almost never. These chronically irritable children almost never converted to adult bipolar disorder. Well, in one of the key follow up studies cited in the sources, only one out of 84 youths who presented with this chronic irritability converted to a manic or hypomanic episode later in life. One out of 84 contrast that with a narrowly defined true bipolar comparison group, where 58 out of 93 youths converted to adult mania, and that is a night and day difference. 00;25;51;27 - 00;26;16;22 Unknown So if they weren't bipolar, what did they actually have? What did they grow up to suffer from? The SMD cohort disproportionately converted to unipolar depression, what we commonly call major depressive disorder, and generalized anxiety, anxiety and depression. The data proved that chronic explosive irritability in childhood is not a developmental precursor to mania, is actually a developmental precursor to severe anxiety and depression. 00;26;16;23 - 00;26;44;23 Unknown That realization is just devastating when you think about the treatment they were receiving. It really is. The entire premise of prescribing an anti anticonvulsant was biologically flawed. From day one. These children were being heavily medicated for a disease they did not have and were never going to develop. And the scientific consensus shifted so dramatically based on this longitudinal data that the American Psychiatric Association was forced to take action to halt the false positive epidemic. 00;26;44;25 - 00;27;09;25 Unknown They had to fix the manual right. When they published the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders, the DSM five. In 2013, they created an entirely new diagnostic category specifically to capture these kids. And what do they call it? They called it disruptive mood dysregulation disorder, or DMD. And the most important part of that correction is where they placed DMD in the manual. 00;27;09;25 - 00;27;32;18 Unknown They didn't put it in the bipolar chapter. No he didn't. They placed it deliberately under the umbrella of depressive disorders. The medical establishment finally codified that this childhood irritability was rooted in depression and anxiety. The nose successfully corrected itself. The textbooks were finally fixed. But you know, that still leaves the question of the medication itself. What happens when you test this drug on the correct population? 00;27;32;19 - 00;27;57;12 Unknown Right. Because researchers eventually did run a trial on kids who actually had true narrow phenotype bipolar disorder. Yes. A rigorous study called the Treatment of Early Age Mania trial, or the Team study, the teens study. They found pre pubertal children with strictly defined bipolar II disorder. And they compared Dial Pro X against lithium and against an atypical antipsychotics called risperidone. 00;27;57;14 - 00;28;17;28 Unknown And what did they find. The results of the team study dismantle the legacy of the mood stabilizer even further. In a direct head to head comparison on the correct pediatric population, dial Pro X finished. Dead. Last. Again. Dead last for a spare. Don't outperformed both Lithium and Divo Pro X, making Divo Pro X the least effective biological agent of the three. 00;28;17;28 - 00;28;55;03 Unknown So to synthesize this massive medical detour, the 2009 pediatric trial didn't fail because the deeper coat molecule suddenly forgot how to work in a teenage brain. It failed because the children enrolled were suffering from ADHD and severe developmental anxiety, not mania. And when researchers finally did find the kids with the correct illness depicted still ended up being the worst tool for the job, the field took an acute 21 day adult anti manic drug, rebranded it as a lifelong mood stabilizer, and prescribed it off label to an entire generation of children who were fundamentally misdiagnosed. 00;28;55;03 - 00;29;15;20 Unknown When you look at a failure of that magnitude, I mean millions of prescriptions, hundreds of thousands of misdiagnosed kids, completely failed clinical trials. You naturally assume there would be massive legal and regulatory repercussions. You'd think someone has to pay the piper. Somebody has to answer for this. And this brings us to the fascinating tension between the legal reality and the ethical gap. 00;29;15;20 - 00;29;44;16 Unknown Because while the DSM eventually corrected the medical textbook, the legal and regulatory systems just allowed the fallout to be quietly swept under the rug. Let's talk about the DOJ settlement, because in May 2012, Abbott Laboratories, the manufacturer of depicted, entered into what on paper looks like a massive accountability event. They agreed to a $1.5 billion global criminal and civil resolution with the US Department of Justice for the unlawful promotion of the drug. 00;29;44;18 - 00;30;08;15 Unknown A billion and a half dollars is a staggering number. When the average person reads that headline, they assume the system worked perfectly. Yeah, they assume justice was served like the company got caught illegally pushing an unproven drug onto a massive population of children, and they paid a massive penalty for it. But when you dive into the actual agreed statement of facts in the settlement documents, the story completely changes. 00;30;08;15 - 00;30;34;26 Unknown It really does. The criminal component of that $1.5 billion resolution consisted of a $700 million fine and forfeiture for a misdemeanor misbranded count. Okay, but if you read the criminal charges carefully, you will notice a glaring omission. The criminal charge focused almost entirely on the company's off label marketing for two very specific uses agitation and aggression in elderly dementia patients and schizophrenia. 00;30;34;27 - 00;31;06;20 Unknown Wait, so the criminal charge completely omitted the entire pediatric and adolescent bipolar epidemic? Completely omitted. There was no criminal accountability for marketing to kids. Zero. The pediatric issues do show up in broader civil allegations and some state level consumer protection lawsuits, but they were entirely absent from the admitted criminal conduct. How does a pharmaceutical company escape criminal charges after their drug is widely prescribed to a vulnerable pediatric population, based on a totally failed clinical trial? 00;31;06;21 - 00;31;32;11 Unknown I mean, that makes no sense. This is where we have to examine two massive structural legal loopholes that basically dictate how drugs are marketed and paid for in the United States. Let's break down the first loophole, which involves a law called the Best Pharmaceuticals for Children Act, or BPC. Yeah, the BPC. To understand why this law exists, you have to realize that historically, drug companies hated running trials on children. 00;31;32;12 - 00;31;51;28 Unknown They avoided it like the plague because it's incredibly expensive, it's ethically fraught, and the market size is usually way smaller than for adults. So for decades, pediatricians were just guessing at doses, you know, cutting adult pills in half. Congress wanted to fix this. So they created the BPC to dangle a massive financial carrot in front of the pharmaceutical industry. 00;31;52;02 - 00;32;18;29 Unknown And the incentive structure by the BPC is profound. If the FDA issues a written request for pediatric data on a medication, and the pharmaceutical company agrees to run the trial, the company is rewarded with a six month extension on their exclusive patent rights for that drug. Six whole months for a blockbuster medication generating billions of dollars in revenue and extra six months of monopoly protection is incredibly lucrative. 00;32;18;29 - 00;32;38;23 Unknown It's huge. But the critical flaw in the laws that it rewards the attempt, not the results, are exactly the BPC grants that six month patent extension simply for running the trial and reporting the data back to the FDA. It does not require the trial to be successful. That distinction is the shield Abbott used. Oh wow. The ran the Wagner 2009 pediatric trial. 00;32;38;24 - 00;33;05;07 Unknown As we discussed, it was a complete failure. But Abbott took that null result, submitted the data to the FDA, and the FDA subsequently updated the official prescribing label to state that the drug was not proven effective in children. So they just updated the label, right. Abbott followed the procedural rules perfectly because they updated the fine print on, like, page 14 of a massive prescribing pamphlet that almost no patient ever reads. 00;33;05;07 - 00;33;29;14 Unknown It wasn't considered a crime. They disclosed the failure. Legally speaking, fraud requires concealment or active deception. If you look at other pharmaceutical companies from that era that did face criminal charges regarding pediatric marketing companies like GlaxoSmithKline with Paxil or Forest Laboratories with Selecta, what did they do? Those companies actively suppress negative trial data, or they ghost wrote articles to hide failures. 00;33;29;15 - 00;33;52;26 Unknown Abbott didn't do that. Abbott did not hide the data. They filed it with the regulator. Exactly because they legally disclosed the failure on the label. They could not be criminally charged for fraud regarding the trial results, and they still legally secured their lucrative patent extension. That is a staggering loophole. Basically, we ran the test. It completely failed. We admitted it in the fine print. 00;33;52;27 - 00;34;16;08 Unknown Now please give us our hundreds of millions of dollars in extended monopoly profits. It's a perfect legal strategy. And that brings us to the second massive loophole, which explains how the government ended up paying for all these prescriptions, even though the drug wasn't approved for kids. Right. The Medicaid compendia provisions. What is that? It is a highly obscure but incredibly powerful mechanism in federal health care law. 00;34;16;11 - 00;34;40;15 Unknown Under this provision, state Medicaid programs are legally required to reimburse prescriptions for off label uses if those specific uses are supported by recognized medical compendia. Let's clarify what a compendium actually is for you. Listening. It's basically a massive authoritative reference book or database, like drug decks, that lists what drugs are commonly used for in everyday medical practice, regardless of official FDA approval. 00;34;40;16 - 00;35;10;06 Unknown Think of it as an encyclopedia of clinical consensus. If a sufficient number of doctors begin prescribing a drug off label for a certain condition, in this case for pediatric irritability, the editors of these compendia will take note of that trend and write it into the database as a recognized use. It's a bizarre feedback loop. It's like a restaurant being legally forced to serve a secret menu item just because enough customers wrote the recipe on a napkin and passed it around. 00;35;10;07 - 00;35;33;06 Unknown That's a great way to describe it, because the psychiatrists in the 90s started prescribing it en masse. It became a recognized use in the reference books, and once it's in the reference books, Medicaid is legally forced to pay for it. And because Medicaid is legally mandated to reimburse these claims based on the compendia listings, the pharmaceutical company cannot be accused of causing the submission of false claims to the government. 00;35;33;06 - 00;35;59;06 Unknown For those specific off label prescriptions, the compendia basically shield them from liability, so they navigated the legal architecture flawlessly. Floor. They followed the letter of the law. They updated the label with the negative result. They relied on a bureaucratic loophole that forced Medicaid to keep paying the bills, and they kept all the profits. The legal architecture cares deeply about technical compliance and disclosure to the regulator. 00;35;59;10 - 00;36;23;16 Unknown It does not, however, mandate that community psychiatrists actually read the newly updated label. It does not automatically recall prescriptions when a long term trial fails. This reveals a massive structural chasm between strict regulatory compliance and the on the ground reality of patient care, which leaves a massive human element to this story that the legal system completely ignores. Absolutely. 00;36;23;16 - 00;36;49;17 Unknown We can analyze FDA loopholes and trial statistics all day, but we really have to bring this back to the very real people caught in the machinery of this systemic failure. The source material introduces a chilling term for this specific demographic. They call it the missing generation, the missing generation. We are talking about hundreds of thousands of youths who were diagnosed under that broad, chronically irritable phenotype in the 1990s and early 2000. 00;36;49;22 - 00;37;10;09 Unknown They were put on Devil Pro X and then they just stayed on it. Nobody ever went back to check on them. When the psychiatric community published the DSM 5 in 2013 and corrected the diagnosis to DMD, they essentially moved the diagnostic goalposts. They fixed the textbooks and ensure that the next generation of irritable children would be diagnosed more accurately. 00;37;10;10 - 00;37;32;02 Unknown Right. But what about the kids already on it? They did absolutely nothing for the patients who had already been captured by the flawed diagnosis. There was no systemic recall, no mandate from the FDA or the APA, requiring doctors to reach out to these young adults and reevaluate why they were still taking an anticonvulsant. And taking this drug for years or decades is not a benign intervention. 00;37;32;04 - 00;38;01;08 Unknown I mean, the risk calculus is severe. We are talking about exposing patients to life altering risks for a disease. They likely didn't even have. The risk profile of Kreuk. Sodium is intense. It carries boxed warnings, the FDA's most stringent level of caution for hepatotoxicity, which is potentially fatal liver damage and for life threatening hemorrhagic bank re Titus. And the metabolic and reproductive risks are particularly brutal, especially for the young females who are caught up in this diagnostic wave. 00;38;01;10 - 00;38;29;07 Unknown They really are. Chronic valproate exposure in adolescent girls and young women is heavily associated with severe endocrine disruption. It is a known trigger for polycystic ovary syndrome, or PCOS, which causes massive weight gain, metabolic syndrome and fertility issues. That's awful. Furthermore, the molecule is a severe terrarium. If a woman becomes pregnant while taking it, it dramatically increases the risk of neural tube defects and severe cognitive impairments in the developing fetus. 00;38;29;09 - 00;38;50;19 Unknown The risks are so high that current prescribing guidelines require strict, highly monitored pregnancy prevention programs for any one of childbearing potential taking the drug. Yes. Very strict. So you have a massive cohort of young people exposed to liver failure, metabolic syndrome and birth defects, all to take a drug that failed its pediatric trial to treat a disease they never actually had. 00;38;50;20 - 00;39;13;01 Unknown It is an absolute tragedy. It is a profound systemic failure. And this brings us to the deeply personal anchor of our source material, this entire research synthesis, all these disparate threads of clinical data and FDA history were assembled by a researcher named Bret Kerr. Right. And he didn't research this from the detached safety of an academic tower. He lived it. 00;39;13;01 - 00;39;36;06 Unknown Bret Kerr's personal case study is honestly the heartbeat of this deep dive. He was diagnosed with bipolar disorder at age 15, right in the dead center of the 1990s pediatric epidemic. Caught right in the net. He was prescribed depth, and he stayed on it for nearly 30 years three decades of continuous exposure to a potent anti manic anticonvulsant, all predicated on an adolescent diagnosis from an era. 00;39;36;07 - 00;40;00;14 Unknown We now recognize as fundamentally flawed. But the most fascinating part of Bret story is how he finally broke the cycle and got off the medication. It introduces a brilliant, very modern twist to this historical medical mystery. In April 2025, Bret used artificial intelligence to help him figure out what was wrong. This is a remarkable demonstration of how technology is shifting the landscape of patient advocacy. 00;40;00;16 - 00;40;24;00 Unknown According to the timeline in his records, Kerr had been experiencing long term cognitive slowing, chronic fatigue and significant issues with his working memory, and for years he simply assumed these symptoms were the natural result of getting older, or perhaps residual damage from his underlying illness. He had never thought to interrogate the medication itself, which makes perfect psychological sense if you think about it. 00;40;24;00 - 00;40;46;16 Unknown If you've been taking a pill every day since you were 15 years old, it just becomes the background noise of your existence. You don't question the wallpaper in your childhood home. It's just always been there. That's a great point. It's just normal to him. But in April 2025, a shift occurred. He prompted ChatGPT, asking him to search for patient accounts of long term difficult use, potential misdiagnoses from the 90s and cognitive side effects. 00;40;46;16 - 00;41;16;04 Unknown And what did it find? The AI synthesized the scattered medical literature and returned a comprehensive report that perfectly mirrored his lived reality the working memory deficits, the emotional blunting, the fatigue. So the AI took his diffuse, unstructured suspicion and organized it into a highly specific biological hypothesis. Exactly. But what I love about this story is that he didn't just read the AI output and throw his pill bottles in the trash, because that would be incredibly dangerous with a drug like this. 00;41;16;05 - 00;41;38;03 Unknown Oh, absolutely. He was exceptionally methodical. He understood the limitations of AI. He demanded that the system provide peer reviewed citations for every claim. He fact checked it. He used the AI as a research assistant to build a formal, strictly evidence based PDF packet. He then took this physical packet to his treating physician to advocate for a change in his care plan. 00;41;38;05 - 00;41;58;15 Unknown He did not use the AI to replace his doctor. He used it to educate himself so he could partner with his doctor, and that evidence based approach worked. He presented the history of the failed trials, the diagnostic shift to DMD, and his own symptom profile. His doctor agreed and approved a medically supervised taper, a very safe approach. Right over several months. 00;41;58;15 - 00;42;29;18 Unknown He slowly and safely weaned off the medication, completing the taper in August 2025 and following the complete discontinuation of the molecule, Kerr reported significant subjective improvements. He documented better working memory, increased mental energy, and a noticeably faster recovery time. After periods of sustained cognitive effort, the chemical brake pedal had finally been lifted. Now, obviously, we have to insert a massive scientific caveat here, and to Brett's immense credit, he explicitly states this caveat in his own research synthesis. 00;42;29;19 - 00;43;03;05 Unknown Yes, the epistemological caution is vital here. Kerr rigorously self corrects the initial overconfidence that an AI might generate. A chatbot might read his symptom list and definitively declare depict, cause all of this right? But Kerr's finalized research explicitly notes that an N of one, a single personal observational account, cannot definitively prove biological causation. A single story can't definitively prove the exact magnitude of the drug's effect on his specific brain, and it can't retroactively prove that his original diagnosis at age 15 was totally incorrect. 00;43;03;05 - 00;43;43;08 Unknown Without a full modern neuropsychological reassessment, exactly. Group level clinical trials describe the statistical averages of populations. They do not dictate the absolute reality of individuals. However, Kerr's journey perfectly illustrates how AI is evolving. It's moving from being a simple tool for personal symptom checking into a powerful catalyst for uncovering decades old systemic medical oversights. The AI helped him ask the exact question he had been conditioned not to ask for 30 years, and that single personal question unlocked the entire historical reality of the pediatric bipolar epidemic, the null trials and the DOJ resolution. 00;43;43;08 - 00;44;05;07 Unknown If we step back and look at this entire story, it really forces you to ask, what does this mean for you? Why should you care about a drug approval from 1995 and a psychiatric fad from the 90s? You should care, because this narrative exposes a fundamental vulnerability in how we consume healthcare. It ties this massive systemic failure directly back to your individual right and your individual responsibility to advocate for your own medical history. 00;44;05;09 - 00;44;27;14 Unknown It explicitly gives you permission to question legacy diagnoses. If you walk into a clinic today, you are benefiting from current science. But if you were diagnosed with something in 1998 or 2005, the scientific understanding of that disease might have been completely rewritten since then. The scary truth is that the medical system is not designed to call you up and audit your old files. 00;44;27;15 - 00;44;45;25 Unknown No one is going to tap you on the shoulder and say, hey, we change the textbooks ten years ago. Maybe we should rethink your daily medication. You have to be the one to ask the question. The burden of curiosity, unfortunately, often falls entirely on the patient. The health care architecture is brilliantly designed for acute treatment and strict regulatory compliance. 00;44;46;03 - 00;45;20;22 Unknown It is terribly equipped for the longitudinal reevaluation of outdated paradigms. We have been on quite a journey today. We started with a specific molecule, Devil Pro x sodium, that was legitimately, scientifically proven to work for a highly specific three week acute crisis in hospitalized adults. It was and is an excellent fire extinguisher for a severe neurological fire. But through the sheer power of a single undefined linguistic trick, the phrase mood stabilizer, that valid three week indication was improperly expanded by clinical consensus. 00;45;20;23 - 00;46;00;18 Unknown It transformed into a lifelong prescription for millions of adults, completely bypassing the glaring failure of the sponsors own long term maintenance trials. And from there, that unsupported adult extrapolation was recklessly pushed onto an entire generation of children. During the 1990s pediatric bipolar epidemic, a massive cohort of kids who, as longitudinal science later proved, didn't actually have bipolar disorder but were suffering from developmental anxiety and depression when the trial on those kids inevitably crashed and burned, the structural loopholes of the BPC and Medicaid compendia allowed the manufacturer to update the fine print, keep their patent extensions, and walk away with billions. 00;46;00;18 - 00;46;25;13 Unknown Meanwhile, hundreds of thousands of patients were left taking a highly toxic drug for an illness they never had. It is a testament to the inertia of the medical system that it took decades. And in Bret Kerr's specific case, the intervention of modern artificial intelligence to finally look back at the trail of evidence, connect the diagnostic dots, and successfully advocate for a medically supervised exit from a 30 year mistake. 00;46;25;14 - 00;46;48;20 Unknown It really fundamentally alters how you view the certainty of a doctor's prescription pad, which leaves us with a final, slightly uncomfortable thought for you to mull over as we wrap up today's deep dive. If a single clinically invented phrase like mood stabilizer possesses the cultural power to circumvent the need for long term clinical trials for decades, you have to ask yourself about the pills you take every day. 00;46;48;23 - 00;47;09;12 Unknown Think about it what other legacy medications currently sitting in your own medicine cabinet, or your families are resting on foundational trials that lasted no longer than a standard three week vacation. Are we truly treating the underlying biology of a disease, or are we just forever treating the history of a diagnostic label? Keep questioning the consensus. Thanks for joining us on this deep dive.