How to undermine Alzheimer’s research


Stop smiling already.

Uh-oh. As I get older, I’d like to think science will come up with treatments for cognitive decline (don’t worry, I’m not showing any symptoms…yet. I don’t think. How would I know?), and Alzheimer’s is serious problem. Judging by the fact that we always get a couple of seminars on Alzheimer’s from our graduating seniors, it’s of concern to even young people. Unfortunately, every prospective drug against the disease seems to flop in clinical trials. It’s entirely possible that 16 years of research has been misled by one study that identified a candidate amyloid protein as the causal agent.

The first author of that influential study, published in Nature in 2006, was an ascending neuroscientist: Sylvain Lesné of the University of Minnesota (UMN), Twin Cities. His work underpins a key element of the dominant yet controversial amyloid hypothesis of Alzheimer’s, which holds that Aβ clumps, known as plaques, in brain tissue are a primary cause of the devastating illness, which afflicts tens of millions globally. In what looked like a smoking gun for the theory and a lead to possible therapies, Lesné and his colleagues discovered an Aβ subtype and seemed to prove it caused dementia in rats.

Why did it have to be the University of Minnesota?

That initial paper that set the field charging off in a specific direction seems to have been fraudulent.

A 6-month investigation by Science provided strong support for Schrag’s suspicions and raised questions about Lesné’s research. A leading independent image analyst and several top Alzheimer’s researchers—including George Perry of the University of Texas, San Antonio, and John Forsayeth of the University of California, San Francisco (UCSF)—reviewed most of Schrag’s findings at Science’s request. They concurred with his overall conclusions, which cast doubt on hundreds of images, including more than 70 in Lesné’s papers. Some look like “shockingly blatant” examples of image tampering, says Donna Wilcock, an Alzheimer’s expert at the University of Kentucky.

The authors “appeared to have composed figures by piecing together parts of photos from different experiments,” says Elisabeth Bik, a molecular biologist and well-known forensic image consultant. “The obtained experimental results might not have been the desired results, and that data might have been changed to … better fit a hypothesis.”

Lesné has gone silent. The university is investigating. Lawyers are, I’m sure, standing by with bated breath.

The evidence is built around Western blots, which are used to resolve individual proteins from a sample. A bunch of the published (and some of the unpublished) data show unmistakeable, unambiguous evidence of tampering, and someone in that lab was clearly going into the data and patching it up to look more convincing. Human eyes aren’t very good at detecting slight variations in a semi-random smear of pixels, but computers excel at it, and the evidence of copy/pasting and merging jump out at you.

Why does anyone pull this kind of crap with their data? If the raw data doesn’t show it, if it can’t be extracted with a statistical analysis of the original image, it doesn’t exist. You can’t compensate for a negative result by artificially pasting the result you wanted in place.

This is a catastrophe. One ambitious researcher faked data in order to get a paper in Nature, and now it’s a quarter billion dollar industry built on a false foundation.

The Nature paper has been cited in about 2300 scholarly articles—more than all but four other Alzheimer’s basic research reports published since 2006, according to the Web of Science database. Since then, annual NIH support for studies labeled “amyloid, oligomer, and Alzheimer’s” has risen from near zero to $287 million in 2021. Lesné and Ashe helped spark that explosion, experts say.

The paper provided an “important boost” to the amyloid and toxic oligomer hypotheses when they faced rising doubts, Südhof says. “Proponents loved it, because it seemed to be an independent validation of what they have been proposing for a long time.”

Great. Forgery and confirmation bias make a terrific pairing.

Comments

  1. wzrd1 says

    I’d say more than undermine, more like obliterating by disgrace an entire field of research on a major disease.
    This will likely be an even greater disaster for research into the disease than the falsified research that “proved” the 1918 influenza pandemic was caused by bacteria, generating much confusion and erroneous research into a viral cause (the existence of viruses still being a wild theory at the time).
    Fuckmuffins, what a mess!

  2. says

    I love this detail:

    The attorney’s clients—two prominent neuroscientists who are also short sellers who profit if the company’s stock falls—believed some research related to Simufilam may have been “fraudulent,” according to a petition later filed on their behalf with the U.S. Food and Drug Administration (FDA).

    Shorting the stock seems pretty badass.

  3. Louis says

    The FDA’s approval of aduhelm was…

    …well, let’s just say that even in the more fervent bits of my industry it was met with a remarkable amount of scepticism. And an equally remarkable amount of “I have a bad feeling about this”.

    Alzheimer’s/dementia treatments are unlikely to materialise any time soon (you know, “Soon(TM)” ) but the market is potentially enormous, so despite the ridiculous difficulty of developing treatments, especially small molecule treatments intended to be given around onset of symptoms (or after), there’s a lot of money going into it. And as this article shows, not all of it is being used honestly.

    This pisses me right off for a lot of reasons, and I know this will get a sarcastic “boohoo”, but there are tens of thousands of hard working, good, ethical scientists and medics working in pharma and this shit not only tars us all with a bad brush, but (more importantly) it sets the development of effective treatments back. That’s the true crime, and yes the overwhelming majority of us give a shit about it. There ain’t fortune and glory in the labs and desks of R&D* compared to the executive suites and the marketing offices.

    Unless they’ve forgotten to send my Big Pharma Shill cheques through. In which case: Bonus!

    Louis

    *Don’t get me wrong though, it’s not awful when you’re a bit more senior. it’s not lawyer/medic money though. And it’s nothing remotely like marketing money.

  4. chris61 says

    Almost every case of research misconduct I’ve ever heard of has included inappropriate manipulation of Western blot images.

  5. Louis says

    Incidentally, the amyloid hypothesis has been thought to be very very shaky for a long while. The lag/lead time of drug discovery is one of the reasons it has been kept alive so long. The difficulty of getting drugs into the brain that do anything even vaguely useful looking is another complicating factor that’s extended this hypothesis.

    Louis

  6. kome says

    The incentive structure in science needs to change. We need to encourage more double-checking, replication, and re-examination of others work and less about trying to be a rockstar propelling the field forward with your revolutionary ideas. We need to encourage more corrections and retractions. We need to see failures of replications as successes in science rather than failings of researchers’ character. We need to encourage people to slow the fuck down with their research so that it is done right, not published quickly. All data must be made available in an online repository to be published (after taking appropriate steps to anonymize things like patient or participant identifying information). We need to encourage publishing less often, but higher quality work that thoroughly examines the research question(s) of the researchers. We need to give reviewers more time to conduct reviews and authors more time to sufficiently respond to reviewers’ critiques.

    We need to utterly destroy the myth of the lone genius, the publish-or-perish mentality, and easily gamed quantifiable metrics as determinants of productivity or importance (e.g. H-index, impact factor).

  7. says

    From the Science article:

    Hundreds of clinical trials of amyloidtargeted therapies have yielded few glimmers of promise…; only the underwhelming Aduhelm has gained FDA approval. Yet Aβ still dominates research and drug development. NIH spent about $1.6 billion on projects that mention amyloids in this fiscal year, about half its overall Alzheimer’s funding. Scientists who advance other potential Alzheimer’s causes, such as immune dysfunction or inflammation, complain they have been sidelined by the “amyloid mafia.” Forsayeth says the amyloid hypothesis became “the scientific equivalent of the Ptolemaic model of the Solar System,” in which the Sun and planets rotate around Earth.

    Incidentally, there’s an article coming out in a couple weeks about a study showing flu vaccines could reduce the risk of developing Alzheimer’s.

  8. says

    I noticed this in the Daily Kos article as well:

    He became a leader of UMN’s neuroscience graduate program in 2020, and in May 2021, 4 months after Schrag delivered his concerns to NIH, Lesné received a coveted R01 grant from the agency, with up to 5 years of support. The NIH program officer for the grant, Austin Yang—a co-author on the 2006 Nature paper—declined to comment.

    How the hell is that allowed?

  9. says

    This is wild:

    But even before Schrag’s investigation, the spotty evidence that Aβ*56 plays a role in Alzheimer’s had raised eyebrows. Wilcock has long doubted studies that claim to use “purified” Aβ*56. Such oligomers are notoriously unstable, converting to other oligomer types spontaneously. Multiple types can be present in a sample even after purification efforts, making it hard to say any cognitive effects are due to Aβ*56 alone, she notes—assuming it exists. In fact, Wilcock and others say, several labs have tried and failed to find Aβ*56, although few have published those findings. Journals are often uninterested in negative results, and researchers can be reluctant to contradict a famous investigator.

  10. Matt G says

    As appalling as this is, how is it possible that the fraudulent work at the foundation of this research was not discovered sooner? People doing related research should have found themselves unable to replicate the results, even if not doing the identical experiment.

  11. says

    A picture of Lesné is really starting to emerge:

    Questions about Lesné’s work are not new. Cell biologist Denis Vivien, a senior scientist at Caen, co-authored five Lesné papers flagged by Schrag or Bik. Vivien defends the validity of those articles, but says he had reason to be wary of Lesné.

    Toward the end of Lesné’s time in France, Vivien says they worked together on a paper for Nature Neuroscience involving Aβ. During final revisions, he saw immunostaining images—in which antibodies detect proteins in tissue samples—that Lesné had provided. They looked dubious to Vivien, and he asked other students to replicate the findings. Their efforts failed. Vivien says he confronted Lesné, who denied wrongdoing. Although Vivien lacked “irrefutable proof” of misconduct, he withdrew the paper before publication “to preserve my scientific integrity,” and broke off all contact with Lesné, he says. “We are never safe from a student who would like to deceive us and we must remain vigilant.”

    According to the article, Ashe hired Lesné straight out of this program. Did Vivien not tell anyone?

  12. raven says

    It is more complicated than just this one study, which appears so useless it could be ignored.
    There is other evidence suggesting that the amyloid protein plays a role in Alzheimers disease. One is a large number of different types of transgenic mice with human amyloid protein genes.

    These various mouse models do have problems replicating the human disease.
    “Transgenic mouse models have also been troubled by the difficulty of producing the full spectrum of AD pathologies, including neuronal loss. ”
    Here is a review of the various mouse models written for a general medical audience with the pluses and minuses of the models discussed.

    Mt Sinai J Med. 2010 Jan-Feb; 77(1): 69–81.
    Transgenic Mouse Models of Alzheimer’s Disease
    Gregory A. Elder,1,3,4 Miguel A. Gama Sosa,2,3 and Rita De Gasperi2,3

    Abstract
    Alzheimer’s disease is the most common cause of senile dementia in the United States and Europe. At present, there is no effective treatment. Given the disease’s prevalence and poor prognosis, the development of animal models has been a high research priority. Transgenic modeling has been pursued on the basis of the amyloid hypothesis and has taken advantage of mutations in the amyloid precursor protein and the presenilins that cause familial forms of Alzheimer’s disease. Modeling has been most aggressively pursued in mice, for which the techniques of genetic modification are well developed. Transgenic mouse models now exist that mimic a range of Alzheimer’s disease–related pathologies. Although none of the models fully replicates the human disease, the models have contributed significant insights into the pathophysiology of β-amyloid toxicity, particularly with respect to the effects of different β-amyloid species and the possible pathogenic role of β-amyloid oligomers. They have also been widely used in the preclinical testing of potential therapeutic modalities and have played a pivotal role in the development of immunotherapies for Alzheimer’s disease that are currently in clinical trials. These models will, without a doubt, continue to play central roles in preclinical testing and be used as tools for developing insights into the biological basis of Alzheimer’s disease.

  13. raven says

    There are single gene inherited forms of Alzheimers disease. It happened to one of my friend’s father.
    One of these genes is the amyloid protein gene itself.
    The other two are involved in the metabolism of this protein.

    https://www.nia.nih.gov/health/alzheimers-disease-genetics-fact-sheet

    Early-Onset Alzheimer’s Disease
    Early-onset Alzheimer’s disease is rare, representing less than 10 percent of all people with Alzheimer’s. It typically occurs between a person’s 30s and mid-60s. Some cases are caused by an inherited change in one of three genes.

    The three single-gene mutations associated with early-onset Alzheimer’s disease are:

    Amyloid precursor protein (APP) on chromosome 21
    Presenilin 1 (PSEN1) on chromosome 14
    Presenilin 2 (PSEN2) on chromosome 1
    Mutations in these genes result in the production of abnormal proteins that are associated with the disease. Each of these mutations plays a role in the breakdown of APP, a protein whose precise function is not yet fully understood. This breakdown is part of a process that generates harmful forms of amyloid plaques, a hallmark of Alzheimer’s disease.

  14. kome says

    As a side note: This is an interesting week for the clinical neurosciences, what with the Nature paper published earlier this week casting very strong doubt on the role of serotonin imbalances in clinical depression.

  15. raven says

    The amyloid hypothesis for Alzheimer’s doesn’t just rest on old assumptions that scientists are too lazy to question. In fact, it is scientists that are questioning it now.
    There is a lot of data, and a lot of it is confirmatory and a lot of it is contradictory as well.

    It is definitely a huge problem that many drugs and treatments for Alzheimer’s have failed clinical trials. Alzheimer’s is the La Brea tar pits of drug discovery, where new drugs go to die.

    So what causes Alzheimer’s disease?
    I have no idea!!! The people who work in the field don’t seem to know for certain so why should I?

    (I’m in the same boat as PZ Myers. As a boomer, we all hope someone comes up with Alzheimer’s drugs before our brains turn into jelly.)

  16. lotharloo says

    @8 SC:

    A lot of the conflict of interest rules apply to co-authorship up to a limit. E.g., they can disallow you from reviewing if you have been a co-author in the last 5 years or so but I doubt there would be a rule against reviewing a grant submission from a co-author 15 years ago.

  17. PaulBC says

    raven@15

    (I’m in the same boat as PZ Myers. As a boomer, we all hope someone comes up with Alzheimer’s drugs before our brains turn into jelly.)

    The downside is that if they stop mental decline in Boomers (and figure out a few other longevity tricks), the rest of us gonna be stuck with Boomers forever (I was born in 1965 and proudly count myself as GenX thank you, albeit on the old side).

    At a personal level, I would like to see everything cured and everyone leading longer and more fulfilling lives. But at a societal level, I think it is important for each generation to know when to step aside for the next. Death used to make this an involuntary decision. I do fear what happens when this changes (and I realize I’m jumping the gun on that, particularly with recent declines in life expectancy due to COVID).

    On this research in particular, it disgusts me to begin with when people fake results, but what kind of psychopath fakes results and then watches as billions of medical research dollars are spent chasing false dreams? (I’ll be generous and suppose this is one of those “Well I still believe my claim is true. I just had to touch up the results a little to get them out there.”)

  18. bcw bcw says

    A number of people on other sites have commented that the paper in question is focused on a particular form of the A_Beta proteins and there is a lot of likely valid work on other forms. The question of whether these proteins are an effect or cause is much bigger ongoing problem.

  19. Le Chifforobe says

    I’m sorry, but I don’t find the allegations of fraud at all convincing. The news article in Science illustrated them with a single figure, showing high similarity between two close-running bands in a single lane of a western blot. These bands are a bit distorted, I am assuming because there was insoluble gunk loaded with the protein. It is FREQUENTLY the case that multiple protein bands in a single lane are distorted in the same way due to loading errors. Replicated bands in different lanes would be far more convincing.
    Looking for better evidence, I followed the link to PubPeer. I did not find it. The criticisms I saw there of these papers all focused on “anomalies” like straight lines found after increasing the contrast of images from the PDFs of the papers. Karen Ashe uploaded high resolution images of the original figures, and the anomalies are not there. These critics are crying “fraud” in response to digital compression artefacts!
    Y’all been suckered.

  20. ealloc says

    Besides the main stunning implication, I also thought it was interesting how much private money is sloshing around amid this debacle:

    Neuroscientists who are also stock market short-sellers, and are funding studies to take down an alzheimers drug company?

    Other academic scientists being paid 10s of thousands of dollars by these private sources to carry out the investigations?

    “Science” magazine supporting investigations to prove fraud in prominent study published by it’s major (historical bitter) competitor, “Nature” magazine?

  21. dianne says

    PaulBC@17: The downside is that if they stop mental decline in Boomers (and figure out a few other longevity tricks), the rest of us gonna be stuck with Boomers forever

    Even a “miracle cure” drug for AD won’t stop aging and age related mental decline. Also, why not keep the Boomers around for the pleasure of saying, “You sound just like your parents” when they complain about Millennials? (Conversely, any Millennials who are acting annoying should be told, “That’s what the boomers used to say.” Gen X: Born to snark. Yeah, Gen Z’s just like us too.)

  22. dianne says

    Louis @3: The FDA’s approval of aduhelm was…

    …well, let’s just say that even in the more fervent bits of my industry it was met with a remarkable amount of scepticism. And an equally remarkable amount of “I have a bad feeling about this”.

    You give me hope for humanity. I have no fucking idea what neurology was thinking when they approved this. I almost hope there was corruption because I hate to think that someone wrote that review* out of conviction.

    *The one the advisory committee chided them for.

  23. Alan G. Humphrey says

    What I find interesting is the lack of oversight by The Invisible Hand™ of the free market. All those millions of private dollars are supposed to be guided by enlightened self-interest to catch this kind of fraud.

    Oh wait, that hand was busy invisibly clawing those government dollars into the pockets of the self-interested oligarchs.

    So it goes.

  24. kaleberg says

    I follow the pharmaceutical chemistry blog, “In The Pipeline”, which provides something of an insider view of various Alzheimer’s candidates crashing and burning. For the last ten years, it has been like those clips of rockets and airplanes crashing that preface documentaries on the story of flight.

    Researchers have been working on Alzheimer’s for decades now. In the 90s, they released a bunch of “smart” drugs that no one even hears about now. Everything was “smart” back then, smart drugs, smart houses, smart bombs. I remember my neurologist being late for an appointment and apologizing. An Alzheimer’s patient had died, and he wanted to extract fresh brain matter. We both managed to avoid making zombie jokes.

    By now, it’s rather obvious that getting rid of amyloid plaques is not going to prevent or slow Alzheimer’s disease. Drug trials take at least five from candidate chemical to phase 3 trial. It’s probably longer for Alzheimer’s which progresses slowly. Throw in the fact that most drug trials fail, and it’s not surprising that it took this long for anyone to seriously question the amyloid hypothesis.

    It’s sad that so much time was wasted on what is likely a fraudulent hypothesis. If nothing else, it meant fewer neurologists studying fresh brains for clues. The article quotes Elizabeth Bik who has a pretty good record for sniffing out fakery, so I’m inclined to believe that there were real problems with the 2006 paper.

  25. Louis says

    @Dianne #24,

    You may get the impression from me that I am extremely sceptical and generally have a very low opinion of pharmaceutical marketeers/sales people/corporate executives etc. I do. Because I work with them.

    Don’t get me wrong, I have a lot of excellent colleagues. Ethical and brilliant in all ways. Not all corporate people in pharma are venal, financially focussed, blinkered, clueless scumbags. But all venal, financially focussed, blinkered, clueless scumbags are corporate people in pharma! Okay okay, I jest. It’s been a long week!

    The industry is…prepare yourself for a shock…an industry. It’s beautifully enmeshed in global capitalism as we all are, and, short of someone waving a magical stick at it and it becoming the “similarly well funded pharmaceutical charity” we’re stuck with at least some of the attendant evils of the profit motive in some fashion.

    I don’t say that to excuse the excesses or the evils that we all know about, far from it. I think the opposite. I think healthcare is just about the most important human endeavour there is, so pharma not only has to exist, but has to be regulated until the pips squeak. You’ll find a lot of the scientific/research/medical side of the industry has similar views (even if we roll our eyes at the paperwork).

    Here’s a completely selfish industry take that will get missed: When things like aduhelm get approved the way it has been approved (and although this isn’t a perfect first time for this sort of thing, it is, from memory, the worst example), it brings the industry into huge disrepute for the right reasons. I.e. some high level shennanigans have been going on. Political/commercial pressure brought onto the FDA etc. Someone in an office somewhere has convinced themselves that in order to cut huge losses something needs to get to market somehow.

    These sorts of behaviours are not uncommon, take Humira as one example. Genuinely brilliant treatment. Hugely effective, wide spectrum of conditions treated etc. AbbVie maintained it’s life at the top of the pile by cleverly exploiting the patent system, timing the push for new indications, buying out/paying off biosimilar manufacturers etc. Arguably this is responsible business practice. Returns to shareholders, maintains company viability etc. It’s the rough and tumble of a corporation’s fight to survive and do good in the economic environment in which it exists.

    But it’s healthcare.

    Every slight delay to an indication, every tweak to a clinical trial, every delay to a biosimilar hitting the market maintains market dominance and therefore cost to healthcare systems. It can also delay effective treatments reaching patients. So the profit motive acts in a corrosive manner to healthcare.

    Ahhh but without this industry doing this we’d have no drugs etc. True true. We have no viable alternative. But don’t we hear this in politics too? Say what you need to to get elected, then follow your unstated agenda? The art of the possible…

    …or the art of low ambitions. Can’t we do better? Can’t more effective industry/government partnerships emerge that deliver more research and less marketing (see: comparative budgets!)? Can’t the profits be reduced a little bit in order to do better for…oh who are they…I forget…you know…those people. Bloody inconvenient bunch of bastards….PATIENTS! That’s them.

    You may say I’m a dreamer..

    Louis

  26. Louis says

    @Kome #14,

    I haven’t gone into the stats on that paper yet (it does need a good look at), but be very very very careful with it. Just like pharma has an agenda, there still (frustratingly) exists an ideological war between proponents of an “all psychological” (admittedly extreme) version of mood disorders (esp depression) and other versions of mood disorders.

    That’s not to say that the serotonin model of depression is good, like the amyloid hypothesis, it’s not on the firmest of ground, BUT there are too many people willing to throw the baby out with the bathwater on this issue. Which is an error. Equally, while SSRIs etc have been hugely helpful to patients with depression etc, it tends to be only at the more severe end in which the greatest effects are noted.

    There tends to be a slightly naïve view of the biology behind drug function in the pages of our esteemed press. A drug FOR a thing, for example. Hell we all do it, but it’s a bad way of expressing ourselves. Just like we can talk about evolution (adaptation FOR) in more teleological ways than we mean to, or are accurate, the same applies here. We’ve mentioned beta amyloid above, and beta amyloid plaques are definitely found more extensively and often in the brains of people who have had Alzheimer’s. What’s not clear (IIRC) is whether or not they are correlates of the neurological underpinnings of AD, or they are the cause (much shakier now than in years previously). Plaques certainly cause neuronal insult and death, previous neuronal insult (for example, certain metals, influenza infection, gingivitis…) is causative of protein misfolding and therefore plaques, but are plaques the “wound” or the “scab”, or both? That’s trickier. Especially when the neuronal insult/vascular changes for AD that appears in your 70s is happening for people in their 40s (like me! SHIT!).

    It’s not obviously wrong that people have followed up on beta amyloid for AD (or tau for PD…) or serotonin for depression etc. None of these were obviously bad ideas. With psychological disease we are still not out of the dark ages, and I am sorry, but having worked in the area for decades now (professionally and voluntarily) the public conversation is frustratingly dominated by clashing ideologies. Ideologies that, to be blunt, were out of date before I was even born. It’s blatantly obvious that, for example, a 100% biological view of mood disorders (for example) is horseshit, just as is its polar opposite. Does the truth lie at 50%? No. But the muppets who pretend that All You Need are Drugs or depression is 100% about trauma are more concerned with billing than basic understanding. Sorry, I’m bitter, but it winds me up that the conversation is often stuck there when reality is so much more interesting. I don’t blame YOU btw! :-)

    Here’s an example of an issue: My first quick scan of the paper mentioned has no stratification by severity of disease (I may have missed it, like I said, first scan, not gone into the stats yet). It’s already known that for two key reasons this isn’t a good sign. First, as mentioned above, SSRIs are only significantly efficacious (i.e. “effective in trials”) in severe disease. Sure, case data in the real world shows reasonable effectiveness across a wider range of disease presentations, but this is a known limitation of the serotonin model.

    Second the murky depths of diagnosis. Mild/moderate depression is a difficult place to diagnose, and, as treatments have become cheaper, and the case data in the real world shows effectiveness (at worst anecdotally, at best robustly depending on what study you’re looking at) in part because these drugs are being prescribed “easily” (i.e. cheaply). Psychotherapy is “expensive” (it really isn’t), often mental health is seen as the junior partner to physical health (it isn’t), and (to take a UK example) a stressed GP who has 7 minutes to deal with a patient can prescribe something quickly, easily, that’s generally well tolerated and has a known effect size. Perfect? No. Why is this relevant? Mild/moderate disease is heavily represented in the literature, so a lot of the data in any review/meta-analysis will, unless excluded, include all presentations of disease. It is less likely that mild depression has a significant biological underpinning than severe depression for the obvious reasons (and a few less obvious ones). So in a set of data diluted by mild disease, are you likely to see an effect to be found in only a part of that data set?

    This is, like I said, an initial quibble based on a skim read. So I could be entirely wrong. These are methodological issues I’ve seen before, and I’d need to dig deeper to see if I’m on the right track. So apologies to all if I am wrong.

    Just like I don’t trust pharma data uncritically (hello quetiapine!) in this area (or any other), I am appropriately sceptical of the majority of the lit I read because there is still a lot of stigma and ideology out there. Not in the majority of cases, but in enough that it warrants careful scrutiny.

    Louis

    Louis

  27. dianne says

    Louis @27: My knowledge of the health care industry (and yes I’m aware that it’s an industry and that they’re not in it for my health) is from the outside, but I now work in regulatory and have a fairly close view of it. My impression, FWIW, is that there are people in it that are genuinely interested in providing good medications safely and are excited by actual breakthroughs, and all good things. However. I also think that the push to approve regardless of the data comes not only from corporate greed and/or survival instinct, but also from egos: work people who work on a drug sometimes appear personally insulted by criticism of it, even if they don’t have apparent financial interest in the outcome.

    Also, pharma firms seem very susceptible to fashion/fads/what the cool kids are doing. Look at how many PD-1 drugs there are, for example. Did we really need that 25th me too PD-1? Probably not, but we have it anyway. At least the PD-1 drugs work. When there’s a hot new idea that doesn’t work (say, treating amyloid in Alzheimer’s), you lose not just 10-20 years of research from one company’s neurology department, but pretty much everyone’s neurology department’s work.

    In placing blame for the approval of a certain non-active and not terribly safe drug, however, I’d say that there is one more elephant that hasn’t been discussed yet. No, I’m not making snide comments about the Republican Party. Yet. I’m talking about patient advocacy groups. Patients have an even greater desire for a drug to work than the pharma firm that makes it. Losing your money is one thing, losing your brain another. Of course they push for approval of anything that looks even vaguely plausible. And they lobby congress to get it approved. And it just flows downhill from there.

    This is, of course, no excuse for the reviewers writing glowing and inaccurate reviews. The truth ought to be documented even if the higher ups then cave to pressure and approve a drug that, to give a completely random example, improves a marker but makes the symptoms associated with abnormality of that marker worse. Completely random example having nothing to do with approvals of a certain drug that, well, as I said, totally random example.

  28. kome says

    @28
    That’s fair. I don’t expect any single paper (or even single allegation of fraud) to completely overturn a prominent theory in a field. That’s not how any of this is supposed to work. But, science does progress through the resolution of controversy by good faith actors of differing perspectives (and by weeding out bad faith actors… if only there was incentive in research communities to do that). And right now, it seems the clinical side of neuroscience has quite a few big ones on their hands. As I said, must be an interesting week to be a neuropsychologist or neurologist or something. This should motivate researchers in those fields to take a closer look at the foundations of these ideas or to re-investigate the original research questions using newly developed research techniques, to see if the older answers still hold water or were, perhaps, a product of their time.

  29. Louis says

    @Dianne, #29 You work in Reg?

    I feel your pain! :-)

    I’ve never yet been personally insulted by my drugs not working (in R&D terms I mean). I have cried myself to sleep a couple of times. And then got back in the lab. As a wonderful ex-colleague told me once: You have to heave a lot of bricks before you hit a duck.

    Louis

  30. anat says

    Meanwhile evidence is accumulating in support of lifestyle for delaying onset and slowing progression of Alzheimer’s Disease. Some of the best supported interventions are anything that leads to better glycemic control and reduced systemic inflammation. Also making sure one isn’t missing crucial nutrients, including ‘official’ vitamins and minerals but also compounds such as choline. Even aduhelm was only shown to slow down disease progression. People have gotten at least that level of benefit from nutritional interventions and supplementation. Combine that with exercise (nothing extreme, but some combination of aerobic exercise and strength training, any improvement you can introduce and keep up) and sleep. Start early and keep going. Because being in poor metabolic health taxes the brain for years and decades before cognitive symptoms show up.

  31. Louis says

    See what anat said at #32?

    That.

    HIT THE GYM*, PEOPLE! (Says the fat lad! ;-) )

    Louis

    *Not “hit Jim”. I got that wrong for years, and he was quite pissed off.

  32. dianne says

    Louis @31:

    I am not above passing my pain on when appropriate.

    You have to heave a lot of bricks before you hit a duck.

    To extend this analogy, you have to throw even more bricks if you’re being misled by faulty or fraudulent research into heaving the bricks towards the desert. (Not that you don’t hit the occasional lost duck that way. I mean, how many drugs are there out there that you look at and say, “Okay, that worked, but what was the person who thought it was a good idea to try smoking?”)

  33. flange says

    Even worse, this gives the anti-mask, anti-vax, anti-science crowd (if they’re even aware of this bullshit) more live ammo to hasten the stupefying of America.

  34. Louis says

    @Dianne #34,

    Great extension! :-)

    Smoking? Rarely needed. The fumes from the lab and the lackadaisical handling habits people develop with/without gloves are enough…

    Louis

  35. says

    Oh, good grief. I wasn’t going to continue this – I didn’t even post about it in this thread! – but it’s too important. The serotonin thing isn’t a theory or a hypothesis and that it’s not true has been known within psychiatry for decades (which is why Moncrieff takes care to say that the notion continues to be publicly “influential,” not scientifically established). Here’s a selection of posts from my blog from almost a decade ago:

    “Fine, so it’s not valid. It’s still useful!”

    “Spinning the failure of biopsychiatry.”

    “Who said it? Can you tell biopsychiatry’s ‘bashers’ from its proponents?”

    “‘There is no reality’.”

    It’s because the validity of these bogus diagnoses has become entrenched in the public understanding despite their lack of evidentiary support that every few years these “revelations” emerge, only to be swamped by people insisting – in the face of the leading figures in the profession declaring them to be invalid – that no, this is science. Gah.

  36. says

    It’s difficult to describe all of the harms and dangers of clinging to this pseudoscientific model (the latest in a long line of psychiatric pseudoscientific models), but setting aside a number of issues I’ve discussed at great length elsewhere, billions of dollars have been wasted trying to retroactively discover a scientific basis for it, while consistent research pointing to social/political/economic causes of mental distress is sidelined. People could be further investigating research showing the harmful psychological effects of childhood abuse and neglect, racism, patriarchy, homophobia, transphobia, fatphobia, extreme inequality, environmental destruction, sexual and other violence, war, trauma, displacement, grief, bullying, austerity policies, poverty, isolation, hypercompetitive and status-obsessed cultures, authoritarian work environments,…

    I recently recommended a new book by James Davies, Sedated: How Modern Capitalism Created our Mental Health Crisis, which has the most recent bibliography. It focuses on the UK.

  37. says

    Moncrieff and Horowitz at MIA – “Response to Criticism of Our Serotonin Paper”:

    We recently published a paper finding that the serotonin hypothesis of depression (the idea that depression is caused by low serotonin or reduced serotonin activity) is not supported by scientific studies that have been conducted over the last few decades. The serotonin hypothesis was communicated to the public as the “chemical imbalance” theory of depression. In surveys, 85 to 90% of people in western countries report believing that depression is caused by a chemical imbalance.

    We suggest that the idea that depression is caused by low serotonin or a chemical imbalance should no longer be communicated to patients as it is not supported by research.

    This also brings into question what antidepressants are doing: if they are not correcting an underlying chemical problem, as people are often told (“like insulin for diabetes”), then other ways of understanding what they are doing, such as providing hope (the placebo effect) or numbing emotions (a common report by patients) may be more accurate descriptions.

    Psychiatrists in Britain, some of them with career-long relationships with the pharmaceutical industry, responded to our paper’s findings and its implications here, which were then reported in several media pieces covering our paper. We would like to respond to these criticisms.

    We would like to say first that no one should stop their antidepressant medication abruptly—this can be dangerous and is known to cause withdrawal effects, which can be severe and long-lasting in some people, especially those using the medications long-term. If anyone is considering this choice, we advise you to discuss it with your doctor and, if you go ahead, to undertake a gradual and supported reduction as advised by recent Royal College of Psychiatry guidance.

    Contradictory responses—the serotonin imbalance theory was both never supported and also is still supported

    There are a few remarkable aspects of the criticisms to note before we address specific critiques. The first is that the criticisms of our paper were contradictory, with some prominent psychiatrists saying that there was nothing new in our review (“really unsurprising,” “not news”) as it was already understood that depression was not caused by low serotonin. However, other psychiatrists said it was “premature” to dismiss the serotonin hypothesis and that further studies are required (despite this hypothesis having been studied for more than 50 years now). The existence of contradictory viewpoints reveals the cognitive dissonance in the field.

    Disconnect between the public and psychiatrists

    The second notable fact is how disparate the response was from psychiatrists and the public, with most psychiatrists shrugging off the finding as a straw man by saying “I don’t think I’ve ever met any serious scientists or psychiatrists who think that all cases of depression are caused by a simple chemical imbalance of serotonin” and that they are “broadly in agreement with the authors’ conclusion about our current efforts.”

    In contrast there has been an avalanche of interest from the public—with more than a million reads on The Conversation, and widespread media coverage, so that our paper is now amongst the top 600 papers ever shared (out of 21 million papers that have been tracked). This interest likely stems from how widespread the message is that depression is caused by a chemical imbalance and that antidepressants work by fixing this imbalance. Many people, including journalists, have been shocked to find out this is not true, with one presenter commenting “it blows your mind.”

    It may well be the case that psychiatrists have a more “sophisticated” understanding of the role of serotonin than the lay public, but psychiatrists have failed to correct this misunderstanding. Several academics have said that “we never told anybody this explanation.” However, the public clearly is being given this explanation: in England last week, a doctor on BBC radio told the public that in depression “there is a chemical imbalance and antidepressant given at the right time will help with that chemical imbalance.” The same message was given to the public on a leading UK morning television programme earlier in the year by another doctor. It is not surprising that the vast majority of the general public (as shown in surveys) believe this message to be an established scientific fact.

    We know from our analysis of textbooks and journal articles that the idea of low serotonin (the “chemical imbalance”) was widespread in medical literature and remains so in many current textbooks. It was only recently that the Royal College of Psychiatrists in Britain removed its reference to chemical imbalances, describing the theory as an “oversimplification,” but without explaining that there is no proof for low serotonin levels, or indeed for any other neurochemical theory of the causes of depression. The American Psychiatric Association continues to tell the public that “differences in certain chemicals in the brain may contribute to symptoms of depression.”

    Psychiatrists fail to appreciate the enormous impact for patients of being told that depression is caused by a chemical problem in the brain and that antidepressants can fix this problem. Skating over this issue to turn to alternative hypotheses about the cause of depression or the mechanism of action of antidepressants neglects to address the fact that patients have been misled. It is alarming to hear that there is a problem in your brain and it is misleading to suggest that we know there are drugs which can fix it.

    This narrative strongly encourages people to take antidepressants because it seems wholly rational to take a drug which reverses an underlying chemical problem; indeed, it seems irresponsible not to do so. What is being dismissed as trivial semantics by experts has had consequences for the life choices and self-perception of hundreds of millions of patients worldwide. Imagine being told that you had a major problem in your heart that required medication to fix—only to find out that that problem was not truly there.

    For the public, the chemical imbalance has been no straw man or semantic approximation, but something that has guided the direction of their lives, choices, and health. We know that believing that your depression is caused by a chemical imbalance tends to make people more pessimistic about recovery (seeing their symptoms as more chronic and intractable), leads them to believe they have less ability to regulate their moods, and also leads them to believe that medication is a more credible solution than therapy. We should actively counter this myth and remove it from medical information conveyed to patients because it is not supported by evidence.

    The mechanism of action of antidepressants does not matter, as we know that they work

    The other argument raised by critics was that even if antidepressants are not rectifying an underlying chemical problem, they can still be effective by modifying neurotransmitters—and we use many medications whose mechanism we don’t understand. Some critics have said “Many of us know that taking paracetamol can be helpful for headaches and I don’t think anyone believes that headaches are caused by not enough paracetamol in the brain. The same logic applies to depression and medicines used to treat depression.”

    First of all, the analogy is misleading because we know that paracetamol works by targeting the mechanisms that produce pain, and it does not produce an alteration in normal emotions and mental experience. With antidepressants, we do not have evidence that they target the underlying biological basis of depressive symptoms, and they do produce mental and emotional changes which can account for their effects.

    Secondly, we would suggest that how a drug works, or what exactly it does, is crucially important in evaluating whether it is useful or not. With a drug that modifies brain chemistry in ways we do not fully understand, it would be wise to take a cautious approach and be wary of using it for long periods of time on a continuous daily basis. This is a very different proposition from taking a drug that reverses an underlying deficiency.

    With antidepressants, we are looking for heuristics, or rules of thumb, to make sense of what these medications are doing in the context of short-term randomised trials that show marginal differences from placebo (with the vast majority of studies lasting less than 12 weeks). The idea that medications work by rectifying an underlying imbalance is very reassuring. Indeed, who would decline such a “lock and key” treatment? And this seemed to have been the marketing strategy of drug companies in propagating this line. For instance, we are not overly worried about long-term use of insulin in diabetes because supplementing a naturally occurring chemical back to normal levels seems unlikely to be a harmful approach.

    However, if the approach to treatment is now reframed as altering brain chemistry in a system that has no underlying detectable problem (or involves a complex and nuanced alteration of serotonin as yet poorly understood) then we are faced with a very different proposition. The human brain has evolved over millions of years and involves thousands of inter-dependent chemical systems to regulate processes in the body and brain. It is a valid question to ask: what is the effect on the brain of modifying the action of a neurotransmitter in this complex, inter-dependent system, especially in the long term?

    We may be guided in answering this question by the effects of other substances that affect mental processes such as thoughts and feelings, including recreational drugs like alcohol. These tend to cause tolerance from repeated use, and withdrawal effects when they are stopped; this combination is usually termed physical dependence (a state distinct from addiction). Most such drugs also have detrimental effects on things like concentration and memory when they are used frequently or continuously. We know that these theoretical concerns are borne out in practice with the use of antidepressants: there are withdrawal effects—which can be severe and long-lasting in some people—and negative impacts on memory, concentration and sleep, not to mention sexual and other physical adverse effects….

    Much, much more at the link.

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