Wednesday, December 12, 2018

Comments by JohnSmith

Showing 83 of 83 comments.

  • I would like to apologize to Dr. Healy and other readers at MIA for the excessively harsh tone of my remarks on this and several of Dr. Healy’s other recent posts. In reviewing my comments, I believe they were unnecessarily confrontational and in some cases inappropriately cast aspersions on Dr. Healy’s good intent and character. I regret these comments and will maintain a higher standard of civility and respectful behavior in the future.

  • Saul I’d also mention my personal experience here, which of course is anecdotal and thus falls far short of a RCT.

    I had a lot of trouble keeping my level of anxiety under control when I was young, such that it really affected my quality of life. I spent 4 years in therapy with some excellent counselors and gained a lot of insight into the experiences that underlay the problem, but experienced no improvement in symptoms. Amitriptyline shut that problem down. I took it for a decade and it did wonders for me. At that time I was able to stop without a return of symptoms, perhaps the passage of time and dilution of trauma with other experiences did what insight could not. I will say that I experienced some fairly umpleasant discontinuation symptoms, but there is no question in my mind that if Ihad to do it over again, the only thing I would change would be to start amitriptyline 4 years earlier.

  • Hi Saul,

    I guess I was not very clear in stating that I think the role of drugs is to address symptoms and not the underlying issues. Even in a purely biological model it is hard to fathom that something as simple as a drug can correct the trauma of childhood abuse.

    With respect to Steve’s comments and those of many others here, the concept of psychiatrists as a monolithic block that seeks to drug people to protect their profession and drug company clients is outside my personal experience. I’ve interacted with a score or more of them over the last 40 years, and the ones I’ve known are generally warm, compassionate people who bemoan the quality of drugs available (one refers to “the dull misery of dopamine blockade” in describing antipsychotics), hate the fact that third party payers will not reimburse them for counseling, and generally try to do the best they can for their clients given these rstraints. One of them wrestled a suicidal client to the ground when he pulled a shotgun out of his car in the office parking lot, which entailed considerable personal risk. Its also worth noting that most members of the profession chose to undertake additional training to become psychiatists, though as a group members of the specialty make no more than primary care docs. Its hard for me to see self selection of people with the sort of cold blooded mercenary attitudes I often see described here under these conditions, though I am sure there are many sellouts and shills as there are in any profession.

    I agree there is an over reliance on meds, but I think this largely arises from a much broader range of economic forces. Insurance companies want to minimize costs, as do state foster care agencies, nursing homes want to keep patients quiet and compliant, and pharma wants to sell drugs (though most psychiatric drugs will be off patent by year end)

  • Marie, that’s not what it says.

    For there to be proof that “the ADHD medication stopped working”, you would need to see a decline in the difference between a group treated with drug and a group treated with placebo over time. And it would have to be the same groups, not two groups whose composition varied over time in a completely unknown manner.

    What the quote says is that they attempted to mathematically adjust the results to compensate for the changing composition of the groups over time but that the “correction” applied may itself be incorrect, thus rendering the entire body of conclusions for what happened after month 14 suspect.

  • Well, let me try again. Here is one way to think about this.

    When a person has a heart attack, the proximal cause of their symptoms is a blood clot occluding their coronary artery. More fundamentally, the cause is decades of overweight, smoking, and lack of exercise, possibly exacerbated by a genetic predisposition.

    An interventional cardiologist explaining the need for a PCI procedure to a man who has just had an MI might focus on the clot. After discharge from the hospital his cardiologist will counsel him to exercise snd quit smoking.

    If one believes as I do, that the brain is the organ that processes our genetics and experience and produces an output we call a soul, the physical and chemical state of our brain is always the proximal “cause” of the state of our souls, and if we are unsatisfied with that state, it can be said to be “unbalanced”. If I can offer a drug that directly relieves that distress, I am likely to emphasize that proximal cause. That does not necessarily deny the role of the experiences that are the fundamental causes of a persons distress.

  • To be honest I’m really having a hard time understanding why this “did too” “did not” argument really matters. Reading the article, I very much do get the impression that the purpose of anti-psychiatry activists in this debate is to discredit psychiatry by painting the profession as guided by simplistic notions that even a layperson can readily reject on casual inspection. I think the truth is more nuanced than this polemic suggests.

    Several hundred years of scientific research have clearly established the brain as the organ most closely associated with both emotive and higher cognitive functioning. While I think everyone today clearly understands that depression cannot be explained by simplistic notions such as a deficit of synaptic serotonin, asserting an absolute duality of brain and mind constitutes little more than mysticism. Mood and cognition are empirically tied to the biochemistry of the brain by many experiments, including Michael Meaney’s studies showing that mice raised in social isolation (and mice raised by mothers who were raised in social isolation!) exhibit social difficulties in adulthood that are closely correlated with brain biochemical and DNA changes relative to mice raised normally. And of course, evidence for interaction between brain and mind in the opposite direction is well established by the ability of many drugs to impact both emotion and cognition.

    What would be nice to see would be articles more addressing the actual issues, and less focus on what strike me as side issues. Did psychiatrists suggest that depression is due to changes in the biochemistry of the brain? Maybe they did, and maybe they presented it in a grossly oversimplified manner. But it would be nice to see more detailed critique of the actual issues of optimal care for people who have difficulties functioning and less argument about issues intended to present the other side as lacking intelligence, integrity, and common sense. We see enough of the latter in political campaigns.

  • Sorry, I missed your point earlier about the severity analysis. Here is what the original authors had to say:

    “…we addressed in more depth the hypothesis that selection biases might account for the loss of relative superiority of medication. If the most severe cases, expected to have poorer outcome than the less severe cases, were preferentially treated with medication at the 36-month assessment, then this factor may account for its apparent loss of efficacy. The statistical method selected to evaluate this hypothesis was the propensity score analysis. This propensity analysis relies on the assumption that selection biases can be modeled as a simple linear combination of multiple, complex variables, such as ethnicity, previous experience with medication, treatment response, SES, and other variables, which may or may not be correct.

    Its interesting that this attempt to retrospectively compensate for absence of randomization did not find an explanatory effect, but like all such efforts, it depends on whether the authors correctly captured all the relevant variables. As such, it is a pale substitute for an RCT.

  • Well, just as a thought experiment, lets take a hypothetical drug intended to prevent heart attacks.

    The trial begins as a randomized double-blind trial with the primary endpoint of overall mortality at 2 years. It enrolls a population with known heart disease, of which 50% in each arm (drug, placebo) have had a previous heart attack. After 2 years 1% of those in the drug arm and 1.5% of those in the placebo arm have died, with almost all of the deaths being among those who had a previous heart attack.

    The subjects from the drug treatment arm are then rolled over into an open label follow up study of 5 years duration. They are neither encouraged to nor discouraged from continuing to take the study medication. 80% of the sicker patients (those with a prior heart attack) decide to continue on drug, but only 20% of the healthier patients do as they are less worried about their hearts.

    At 5 years follow-up, we compare mortality between the following two groups:

    1) A group in which 80% of the subjects are high risk and have been taking drug
    2) A group in which 80% are low risk and have not been taking drug.

    Group 1 has higher mortality. How do you interpret that result?

  • Lots of people really hate this drug, but I don’t see a big problem.

    1. “It’s disease mongering” – Sure, but regulatory pathways in the United States and every other major country require that a new drug treat a “disease or condition”. In principle there is nothing wrong that I can see with developing a drug that helps people enjoy sex or have more orgasms, but you can’t get such a drug approved unless it is positioned as correcting some sort of deficit. “Disease mongering” in this case is a rational response to an irrational regulatory regime that requires the existence of a “disease” as a prerequisite for drug approval. Drugs that enhance life are simply not recognized.

    2. “It’s a recycled, failed antidepressant”. Who cares? Viagra is a recycled, failed heart medication. It works just fine and allows hundreds of thousands of couples to have better sex.

    3. “It barely works and has side effects”. This is probably the only objection I’ve seen that holds water. But as individuals, people will place different values on an additional “sexual satisfying event” per month, so its hard to set a risk-benefit ratio that is applicable to everyone. Why not let women make their own decisions as individuals?

    4. “Pharma will make billions off a drug that hardly does anything”. Experience shows that people generally stop taking drugs very rapidly unless they experience some benefit that they find meaningful. While I am speculating here, I think this drug will likely be just as much a commercial flop as the once highly hyped antiobesity drugs approved in 2011 that never achieved sales >10% of the original market estimates.

    JMHO.

  • Steve, I have not followed the ADHD area particularly closely, so I do not have an informed opinion about the overall evidence base.

    With respect to science and the brain: I agree, its a very complex organ and our understanding is very rudimentary. We have learned a few things: dopamine antagonists acutely reduce symptoms of psychosis; dopamine agonists are useful for controlling the symptoms of parkinson’s disease; acetylcholinesterase inhibitors can temporarily turn back the clock by a few months in people with Alzheimer’s disease; allosteric GABA agonists are useful for controlling seizures; and so on.

    I think a lot of the problems come in from efforts to force fit a single approach to every individual, and when drugs are used because they are (ironically) cheaper than more humanitarian, individually tailored approaches. I saw a lot of this in the foster care system.

  • Sorry, likewise I responded to your comment below without seeing this one.

    Why do you think the original study design was flawed.

    I don’t know that ADD is a “brain disease”. I think that for most aspect of human behavior and cognition there is a range in which different people fall. If some people are at the extremes of the range, they may find it difficult to function. For example, I used to worry about random stuff so much it made it difficult to function. I took amitriptyline and it made it easier not to do that. When I got older it wasn’t such a problem, and I stopped. For me it worked well, for others it has not.

    I think “diagnoses” are fine as long as they are used as rough guides as to what helps some people with certain characteristics. When they are used to stigmatize, coerce, or fail to recognize individuality and freedom it becomes a problem. JMHO.

  • I don’t know that anybody “muted” it or how it says anything about “money and guild interests”. Fourteen months was the primary endpoint of the trial, and randomization was lost at all points after 14 months. At that point its basically a cohort study with potential for all sorts of confounding factors. For example, the parents of kids with especially severe ADD were probably more likely to keep them on the rigorous medication schedule that worked for the first 14 months than those with kids with milder symptoms. There’s no way to control for that simply by looking at the test scores of kids who continued to adhere to the regimen.

  • James, this was quite an interesting article, thanks for bringing this to my attention as I had not been previously aware of this study.

    On a minor note, I’m not entirely sure I agree that the finding that “this large scale study would provide clear guidance for those using and prescribing drugs to kids” is quite as clearcut as described in your summary. Notably

    1) We know that the 14 week time point was the primary endpoint of the trial. If the results had been positive at 36 months and negative at 14 months, I think we would see much criticism of the study authors here for ignoring the primary endpoint (14 months) and focusing on a secondary endpoint (3o months). Surely if focusing on a secondary endpoint that to obtain a more positive result is unacceptable, doing so when the secondary point is more negative is bad too.

    2) The results post-14 months are intrinsically less reliable because the kids did not stick with their assigned treatments. While the authors performed a post hoc analysis of the level of medication and adherence to assigned treatment in the post 14 month period and found “no effect of medication adherence”, once the kids moved into “regular community treatment” and adherence to the assigned treatment became optional, randomization was lost. Put another way, the kids whose parents decided to continue with intensive medical treatment might as a group differ from the kids whose parents stopped treatment.

    So while I think the 36 month data casts some doubt on the 14 month results, I don’t think they definitively contradict them. BTW, I thought this was a very interesting article, thank you for writing it.

  • True Dr. Hoffman, but I’d say that this same observation applies to almost any body of evidence. One can look at the data for almost any healthcare intervention, that regarding global warming, or that regarding the health impacts of GMOs, and by subtle decisions regarding how to weight various studies and the reliability of their results, support almost any preconceived position.

    In general, diagnoses serve to emphasize the common aspects of human experience, whether psychological or physiological, and to organize and suggest common approaches to problems that have shared aspects. I agree that they should not be used in a simplistic way to cubbyhole human experiences or to gloss over individual needs.

    I’m also aware that many people on this thread have had bad experiences with psychotropics. With children in particular, we know these drugs carry a lot of risk. But I am not aware of any objective evidence that “The evolving adolescent brain will be impaired by the use of medication. ” Rather it seems to me that the use of medication is an issue that should be addressed on an individual basis, taking into account the specific needs and values of the client.

  • Fiachra,

    I hear of a lot of reports of bad reactions to psychotropics that don’t seem to fit with what the clinical trial data shows. I suppose some of this is because the trials are run by the manufacturer, but find it hard to believe this is the whole story given the use of academic clinical sites that are audited by the FDA. I suspect that individual variation in response has something to do with it. And depending on individual values, a single effect may be perceived by some but not others as harmful.

    There does seem to be a strong tendency in the blog world, that if a person is taking a drug, anything bad that happens to them (or anything bad they do) is blamed on the drug. I’m pretty skeptical o that reasoning. I’m sure that some people have bad reactions to these drugs (that seems very clear), but the idea that someone completely lacking violent tendencies is turned into a violent psychopath by a week’s treatment with an SSRI strains my credulity.

    I am glad you are doing better. I have had some rough years myself in the past, and am doing better as well.

  • A National Bureau of Economic Research study comparing changes in antidepressant use with changes in violent crime over time found that those countries with the largest increase in SSRI prescriptions saw the largest decreases in violent crime.

    People on antidepressants are more likely to commit crimes in the same sense that people in the hospital are more likely to die. Its not a treatment effect, its a result of the underlying problems that lead the person to take an antidepressant. In spite of the popularity of the myth of antidepressant-induced violence, there is no data to support it.

  • But surely the relationship between mind and brain is not a simple duality. Michael Meaney has done some fascinating research showing that mice raised in isolation (and mice raised by mothers who were raised in isolation!) have characteristic dysfunctional stress responses in adulthood that correlate with specific changes in neurohormone levels and even in DNA structure. Drugs that acutely reduce hallucinations in people with Parkinson’s disease also acutely reduce hallucinations in people with schizophrenia.

    I’m very much reminded of my high school physics discussion of quantum mechanics. Is an electron a particle or is it a wave? The answer: yes.

  • Hi Dr. Ruckledge,

    I was interested in this article as I used to work at a database company that tracks the progress of drugs in clinical trials, in part by using the clinical trial registry updates. I was surprised by your findings, as it conflicts with my personal experience working with the subset of trials that are conducted for purposes of regulatory submissions of new drugs or new indications for approved drugs.

    Starting at the end of your excel spreadsheet of retrospectively registered trials and working upwards, one finds a phase 3 registrational trial of the antipsychotic drug ziprasidone, registered in January 2006 but beginning in December 2005. In a strictly legalistic sense, this is indeed a “retrospectively registered trial”, but the implication that this retrospective registration somehow allowed for retrospectively changing the endpoints seems unsupported.

    * This was a registrational trial conducted for regulatory approval in the United States, and so the trial design would have been disclosed to FDA prior to beginning enrollment
    * It was a double blind trial, with the blind unbroken until the primary completion date of May 2008. With the allocation of subjects to the treatment arm blinded, one cannot “adjust” the endpoints to optimize the apparent effiacy
    *As the endpoints of the trial were measured after 8 weeks of treatment, no final data for any patient would be available at the time the trial was registered, even if the blind were broken.
    * Large phase 3 trials typically take from 9 months to 1.5 years to recruit the full number of subjects. By the end of January 2006, it is unlikely that more than 50 of the 504 subjects in this trial had even been enrolled.

    Working up the table, one finds similarly that the trials in rows 61, 60, 59, 58, 56, 54, 53, and 52 were double-blind trials for which results would not have been known to the investigators at the time the trial was registered (1-2 months after the start date). Those in rows 57, 55, 51, and 50 were either clearly registered after results were available or the timing at which results became available was ambiguous. I did not examine the other 48 trials in detail.

    What perecentage of these trials overall were double blinded, with the trial registered prior to the Primary Completion date? I would think that this would be a better measure of the potential for retrospective adjustment of the endpoints.

    Thanks for making the raw data available in such a convenient form by the way.

  • I am sure Mr. Whitaker honestly believes every word he says. I also believe that like every other person on the planet, his beliefs are subtley influenced by his financial and career interests. That is why transparency is important

    In terms of Mr. Whitaker’s ethics, I am confident they are very high. I would offer only the very minor criticism that this website, which is supported by donations, apparently provides free advertising for books on which Mr. Whitaker earns royalties.

  • Its not an accusation at all.Its a request for transperancy. COI is not synonymous with corruption or even bias, but empirical studies have shown it is a significant influence. If it weren’t, why would companies spend so much money on docs, and why would it be such a topic of discussion on this website?

    From my POV, writers of popular books about healthcare have their own common financial and career interests that parallel those of psychiatrists. It is a guild as well.Controversy generates notoriety, career opportunities, and financial rewards. The more severe and pervasive a problem undercovered by an investigative journalist, the more controversy and headlines generated. No reporter ever won a Pulitzer Prize, became a household name, or became wealthy by wtiting a book stating “mostly fine, but I found a few things that could be tweaked”.

    In 3 clicks you can go to Dollars for Docs and see how much pharma money was recieved last year by any member of the psychiatric profession. I don’t understand why it would be percieved as an accusation or in anyway threatening to ask for a similar disclosure from others who earn their livelihood as commentators on the field.

  • Just to elaborate my position a bit Katie: I think we all agree that most companies in most fields over-hype the value of their products. In medicine we try to protect patients from this by having a learned intermediary – a doctor – act as a gatekeeper between the drug manufacturer and the patient/client.

    In the case of psychiatry in particular, the role of the physician as a gatekeeper who puts the client’s interests first has been undermined by pharma payments that sometimes run into the hundreds of thousands of dollars. I share your concern about this. $100,000 is clearly enough money to affect anyone’s objectivity.

    For purposes of transparency and comparison, it would be interesting if Mr. Whitaker would share with us his total earnings from book royalties, speaking engagements, etc. related to criticism of the practice of psychiatry to date. I don’t think this is an entirely unreasonable request given the strong focus of much discussion on this site on the affect of pharma payments on the objectivity of psychiatrist viewpoints.

  • Well, I guess we’ll agree to disagree.

    The concept I’m trying to argue here is that if people are getting great benefit from an intervention, they don’t usually quit the trial. As a simple example, in 1 year duration trials of weight loss drugs, the percentage of people finishing the trial is very closely correlate with the average weight loss produced.

    But in any case, good to meet your acquaintance and thank you for your thoughts.

  • BP, I have no doubt that a supportive family structure is a very important and positive thing. I think we agree on that.

    But the study you have presented indicates that 251 people entered the study. They report results for only 50, of whom 32 (13%) were reported to be stabilized in a medication-free state.

    My response is about the same as yours would be if I presented you with the results of a clinical trial of a “wonder drug” performed in 250 patients, defended it on the basis of good results in 32/50 of those patients, and refused to disclose what happened to the other 200.

    Objectivity requires that we hold all studies to the same standards of credibility, whether their results support or undercut our pre-existiing beliefs.

  • Steve, the FDA considers the weight of evidence provided by all trials, though it does consider trials in which a known positive control fails to separate from placebo as a “failed study”.

    If you have an example of a drug that was approved on the basis of two positive studies and 15 that showed harm or no effect, could you share it with us? I’d be fascinated to see it.

  • This was really a weak study. If the same type of trials were carried out pre-2000 and post-2000, the paper’s conclusions would be justified.

    But the pre-2000 trials were mostly seminal studies of new interventions such as statins, the efficacy of which has been independently confirmed in multiple other trials. In contrast, over a third of the post-2000 trials were of HRT, and a majority of the remainder were of incremental strategies such as “2 drugs instead of 1”.

    There might actually have been some shifting of trial endpoints in the pre-2000 period, but if so, this study doesn’t demonstrate it. The vast majority of the pre-2000 trials would have given positive results, and the vast majority of the post-2000 trials would have given negative results, whether the endpoints were pre-specified or not

  • Perhaps a minor point, but the statement in this article that FDA does not consider clinical significance in approval decisions is factually incorrect, and the 20 year old paper cited in support of this statement is at best out of date.

    FDA guidance documents on trial design for different therapeutic areas routinely discuss minimum acceptable thresholds for clinical significance, often providing exact numerical values. The FDA guidance for the development of antiobesity drugs, for example, specifies a minimum average weight loss of 5%.

    In this particular case, setting a numerical threshold is difficult, as the value placed on 0.5 additional “satisfying sexual events” per month will be a very individual one. Overall I think its probably best to allow individuals to make that decision for themselves.

  • Hi BPD,

    Superficially, the results are wonderful for the 51 of 251 patients who finished the study, but the paper doesn’t really speak of what happened to the other 200. This is what is called “responder analysis” in drug development, and it is never accepted by regulatory authorities as proof of efficacy because the usual and logic assumption is that those who did not finish the study are treatment failures.

    While trying to keep an open mind, another thing that made it difficult for me to take this 2014 paper seriously was it’s citation of a paper from 1967 that concluded that hospitalization was increased by anti-psychotic drugs. 1967 is fully 48 years ago, and scores if not hundreds of clinical trials have addressed this issue in the intervening years. The vast majority of these studies reached the opposite conclusion, but are not mentioned. This sort of cherry picking of data to support a point of view undermines my confidence that the rest of the data in the paper is being objectively reported.

    So without intending to be snarky, I guess my answer to your question is that all kinds of pills can produce the results described in this paper for 20% of treated patients.

    Frank, your opinion is clearly an honest one and one you have spent a lot of time thinking about. I agree with you that the marketing of psychiatric drugs turned into a real cesspool. But the clinical data does show that they have some use, and that those treated with drug are less likely than those treated with placebo to be hospitalized or to drop out of the trial.

  • Well, there are anecdotes, but clinical trials demonstrate that intermittent treatment with antipsychotics during periods of symptom exacerbation is less effective than continuous treatment and more effective than non-treatment, with a relative risk for intermittent treatment of 2.5 relative to continuous treatment and 0.37 relative to continuous treatment.

    If the lower dropout rates of people treated with active drug compared to those treated with placebo was due to a withdrawal syndrome when they stopped, one would expect intermittent treatment to be worse than continuous treatment. Its not.

  • BPD, you raise an interesting question, but I think it would be very difficult to design a study that would provide a clearcut, objective answer to your question. I suspect that if one could be designed, it would show examples of both.

    Frank, your response was not particularly helpful in terms of understanding your position. You don’t think the drugs used longterm help anyone. I think the stock market will be flat for the rest of 2015. Since we dont’ know each other well enough to know how to value each other’s opinion, statements like this are not helpful. Why do you think the drugs are never helpful long term and what evidence are you referring to?

  • Uprising, the reason one can make the argument that people stay on the drugs because of efficacy is because thats what they tell you when you ask them. Patients dropping out of clinical trials comparing drug to placebo are always asked why. Dropout rates are consistently higher in the placebo arm, and lack of efficacy is by far the most common explanation given by these individuals.

  • I agree with much of Mr. Whitacker’s statements here, though I would broaden their scope considerably. The “institutional corruption” and COI he describes extend to the entire field of medicine, with practioners being paid piecemeal for performing procedures they themselves recommend. The same considerations apply to Mr. Whitacker’s profession: What journalist or book author has ever undertaken any investigation only to conclude that “There is nothing unusual or troublesome going on here”. Books, magazines and newspapers are sold by provocative headlines and claims of having uncovered scandals that are exceptionally widespread and severe.

    What is needed to ignore the assessments of both those with a financial/career interests in both the overstatement and understatement of the risk-benefit ratio of pharmaceuticals. NICE and the Cochrane group might be reasonable examples of such organizations. Systematic reviews by the former organization have supported a favorable risk/benefit ration for antidepressants in moderate to severe depression and dysthymia, but not in mild, short term depression. The latter group has concluded that certain antipsychotics are useful in the acute treatment of schizophrenia exacerbations, but finds very limited evidence for maintenance treatment with most drugs.

  • While Dr. Healy’s goal of capturing the variability of drug effects on individuals is laudable, his elevation of individual anecdotes above randomized clinical trial data ultimately boils down to a simplistic “if something happened to you while taking a drug, the drug must have caused it” epistemology. Indeed, this is the exact type of reasoning that guided the development of medicine prior to the development of the scientific method, and which supported over 1000 years of treating illnesses of all sorts by phlebotomy. His suggestion that the double blinding of clinical trials “destroys knowledge” ignores the considerable body of well-established knowledge regarding placebo and nocebo effects. In clinical trials of Prozac, 21% of those receiving drug developed headaches, as did 19% of those receiving a sugar pill, and substantial therapeutic effects were seen in the latter group. Placebo controlled clinical trials do not “destroy knowledge”, but rather serve to distinguish effects of drug from those caused by other factors.

    I was also troubled by the degree of artistic license that the article takes with the medical record, including comments such as “100% in SSRI trials experienced genital numbing” and the statement about chili paste, which describes symptoms very different from the sexual dysfunction commonly associated with SSRI use. Historically, Dr. Healy has taken some very courageous stands in pointing out mis-statements and distortions of the medical record by pharmaceutical companies that led to great patient harm. The best approach to combatting these mis-statements and distortions is rigorous truthfulness and careful attention to the facts, rather then the creation of an edifice of opposing mis-statements and distortions.

  • “The problem is that there are 10 trials of Drug Z, not 4. You can’t read the remaining six, because they have never been published” This is only partly true.

    Jones et. al (http://www.bmj.com/content/347/bmj.f6104) found that 68% of large (generally Phase 3) trials are published within 5 years of completion. (5 years is admittedly a long time, but remember that at least 13 months, and commonly up to 20 months, passes between completion of the trial and regulatory approval). While the discussion section in the article attributes non-publication of the remaining 32% to “industry hiding negative results”, an examination of the paper’s supplementary material reveals that some 90% of the unpublished trials are of drugs that were never approved.

  • I’d actually like to offer that to all the folks on this thread. Before criticizing people who welcome deeply troubled children into their homes, risking assault, fire, the torture and killing of pets, and sometimes the sexual abuse of their biological children, try volunteering and doing what they do. Show you can do it better. Otherwise you’re just an obese and out of shape fan sitting in the stands, throwing empty beer cans at real athletes because they don’t meet up to your arbitrary standards of athletic performance. Its not very attractive behavior.

  • Well, no, I’m not saying there is nothing you can do but wait till the entire system is revamped. For one, you could volunteer. The ones with a history of violence are particularly difficult to place. If you want to to that, and feel you can do it without drugs, that’s a wonderful thing. On the other hand, if you just want to criticize people who are doing far than you are, that’s less than ideal.

  • Its not that complicated. The people in the drug treated group were dying earlier for the same reason that they were having psychotic episodes: Because they had more advanced disease. Psychotic symptoms are known to be a symptom of relatively advanced Parkinson’s, and Parkinson’s is a progressive, fatal disease.

    Maybe it would be good for MIA to host an article on how to interpret clinical trial data, and especially the limitations of observational data from non-randomized studies.

  • I think there is an important underlying issue that is not being discussed in this thread, specifically the under-resourcing of child protective services and the foster care system in many if not most states which leads to a high proportion of the use of these drugs.

    In well-intentioned but ultimately profoundly damaging efforts to “preserve the family”, kids who have been removed from their birth home are repeatedly removed to foster care, returned to their birth family, and pulled back out again. The process adds tremendously to the psychological damage caused by the original abuse, and by the time many of these kids are permanently removed from the home, they are horrifically traumatized.

    The problem is further complicated by a profound shortage of people willing to serve as foster parents. At one point the Michigan state legislature actually debated a law to require welfare recipients to serve as foster parents as a condition of aid. What a mess!

    The upshot of all this is that terrible psychological damage is done to kids in the system, they end up tremendously difficult to care for, and the resources and support provided by the state for doing so are minimal. We knew people whose foster kids wiped feces on the wall, assaulted their foster parents, and in one case burned down the home they were living in. This is a lot to ask of foster parents, who are recieving a monthly state stipend of about $200 per kid.

    It is a terrible thing to drug kids, and a very easy thing to criticize. But the volunteers taking care of these kids are doing the best they can, and need to be safe. If you want to do something about this terrible problem, one has to go deeper than simply trying to outlaw the use of drugs. The entire system needs to be revamped to move children out of abusive homes and into stable environments before they become traumatized, and in some cases, violent. There needs to be more resources (other than 15 minutes with a shrink every two weeks) made available to help these kids with their transition, and their needs to be more people volunteering to care for them.

  • “Most drugs are developed in academia” – that would be funny if so many people didn’t believe it. In fact, the NIH’s annual budget for Alzheimer’s disease wouldn’t cover the cost of a single Phase 3 clinical trial. Marcia Angell shoots from the hip, but doesn’t understand where drugs come from any better than I understand nuclear physics.

    If you’d actually be interested in a detailed, extensively referenced, and unbiased history of where currently used drugs came from, I recommend “Drug Discovery – A History” by Walter Sneader. He’s an academic by the way. He details all his primary sources, and you can go look at the original publications for yourself and see what institution the key discoveries were made at. I’ll give you a hint – post 1960, the overwhelming majority were at corporations.

  • Yes, of course, people have made optimistic predictions in the past and they were not fulfilled. Likewise, there were people who were skeptical of the polio vaccine and penicillin. It doesn’t take a PhD in Aristotlean logic to figure out that bringing up such examples doesn’t prove anything. I’ll happily trade an example of mistaken pessimism for every example of mistaken optimism you care to present. Let’s look at the data instead.

    If you look at the survival curves of the immunotherapeutics currently in clinical trials, patients just seem to stop dying about 2 years into the trial. Its too soon to say for sure, but it looks like even with the very early drugs based on this technology, we may be curing 20% or so of patients who present with metastatic cancer. This is unprecedented. With the exception of testicular cancer, metastatic cancer is generally a death sentence.

    http://jco.ascopubs.org/content/32/10/986
    http://www.nejm.org/doi/full/10.1056/NEJMoa1504030?query=featured_home
    http://www.nejm.org/doi/full/10.1056/NEJMoa1504627#t=article

    Of course if you develop cancer and decide that you would rather die than take the chance of discovering that the pharmaceutical industry had done something useful and valuable, that is absolutely your right.

  • Jill, I don’t think its a matter of “back to slash and burn” as having not made the advance yet. Correct me if I’m wrong, but it doesn’t sound like your lab has yet developed inmmunotherapy for esophagael cancer either. Are you claiming to hold the moral high ground because you can’t offer chemotherapy either?

    As for fish oil, there are no RCTs that have shown an effect on CV outcomes. The anti-inflammatory effects of statins are just one hypothesized mechanism for their cardiovascular protective effect, and recent results with Mercks cholesterol uptake inhibit strongly suggest that their effect on LDL at least contributes.

    Steven, I certainly won’t argue that we should add statins to the water supply, but your assessment is dramatically out of synch with that of COI-free expert opinion, including that of the Cochrane Collaboration.

  • Yes, depression is a rare side effect of statin treatment. But I’m curious as to why you believe that your current general ill health is attributable to the statin. Is it possible that it instead results from the fact that you are 10 years older? Statins have been taken by hundreds of millions of people, and I am not aware of any studies that have suggested a general negative effect on overall health. On the other hand, the effects of aging are extremely well-established.

  • Dr. Littrel, I don’t know if you’ve paid much attention to what is going on in industry, but the approach you advocate is not confined to academia.

    Bristol-Meyers-Squibb has developed the antibodies nivolumab and ipilumumab for the treatment of cancer. These antibodies unleash the tumor-specific immune response by antagonizing T-cell checkpoint pathways, and have demonstrated remarkable effects in patients with metastatic melanoma (including complete responses) and have outperformed chemotherapy in several other cancer types with reduced side effects.

    Juno Therapeutics and others are developing varous chimeric antigen receptor modified T-cells for hematological cancers, and have achieved what can only be called extraordinary results in acute leukemia, including a early stage trial in which complete remission was obtained in 91% of patients with relapsed or refractory ALL. Its an extraordinary result.

    Indeed, immunotherapy is front and center in industrial oncology research, and it appears likely that metatstatic cancer will be routinely curable within 20 years.

    So I don’t think your description of “modern medicine is a slash and burn approach” or “an assault on disease rather than aiding the body’s defenses” is entirely accurate. The best science is moving forward and not just in academia.

  • I’d say that if someone hands you a 3 page safety brochure with your new prescription, that’s a pretty good red flag that you are being given something that has important safety issues and you should read it.

    I’m a little unclear on how you reached the conclusion that “deceptiveness” is involved when you give someone a warning and they decline to read it. I’d say handing someone a written warning is pretty direct.

  • Oh boy. Perhaps Dr. Pfieffer could join us and present the results of randomized double blind trials demonstrating the impact of some of these natural substances on the clearance of tuberculosis; on the prevention of death in HIV; on the progression of chronic myeloid leukemia; on the cure of Hodgkin’s lymphoma; on the prevention of hip fracture in osteoporosis; or on the extension of life in metastatic melanoma. Somehow these publications have not shown up in Pubmed.

  • I don’t think statins are a “fad”. They’ve been shown in randomized clinical trials to reduce cardiovascular events and mortality both in primary and secondary prevention. This is not a conclusion reached merely by a treatment guideline group made up of paid speakers for pharma, but by groups such as the Cochrane Collaboration (of which Peter Goetz is a part), AHRQ, and NICE.

    There may well be room for continued scientific debate, but to suggest that the vast amounts of expenditures and personal career investment that have gone into investigating these issues add up to a “fad” is unduly dismissive and fails to engage with the substantial body of research that has been done in this field.

  • Well, as a chemist, I would say that here is no clear dividing line between chemicals found in natural sources and those found in synthetic products in terms of health effects. Tomatoes contain methanol, which is metabolized to carcinogenic formaldehyde in the body. Aflatoxin, one of the most carcinogenic compounds known to man, is found naturally in peanuts. Methycarbamate, another carcinogen, is found naturally in fermented beverages. I could go on at great length, but overall I’d say that for most people who don’t smoke, their biggest exposure to dangerous chemicals comes from eating grilled meat. Heating proteins to 600 degrees results in an array of carcinogenic heterocyclic amines that makes my head spin.

    With respect to informed consent, the patient information leaflet that the FDA requires be provided to every patient recieving an oxy prescription says the following:

    “A long-acting (extended-release) opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.”

    Seems fairly explicit to me. No one gives you a leaflet stating that peanuts may give you liver cancer or that barbequed meat is associated with increased risk of cancer of the bowel, breast, pancreas, liver, and testicles when you buy them.

  • For example, Slide 7 here
    http://echo.unm.edu/wp-content/uploads/2014/10/LHHS-091012-Michael-Landen-State-Epidemiologist-Prescription-Drug-Overdose-Deaths-in-NM.pdf
    shows that illicit drug overdose deaths in New Mexico rose over 3-fold from 1990 to 2002, during which period Rx drug overdose deaths rose by about half. From 2002 to 2009 illicit drug deaths remain flat at 10 per 100,000 population, while Rx drug deaths rise 2.5 fold. (I have not used the 2010 data because of the large proportion of “unspecified” drug deaths).

    Is it a coincidence that the annual growth in illicit drug deaths ground to a halt in 2002, and the growth in Rx drug deaths increased such that the growth rate of total narcotic drug deaths remained constant across the entire 20 year period? Or that the plateauing of Rx drug deaths in 2012 was accompanied by a doubling of illicit narcotic drug deaths?

    The issues are complicated by an interplay between pain patients becoming addicted and what I suspect is a much larger population of recreational drug users who go back and forth between oxy and heroin depending on availability. The growth in Rx drug deaths overall does not seem to have been greatly affected, in New Mexico at least, by the availability of oxycontin beginning in 1995. Indeed almost a decade passed between the commercial availability of oxycontin and the beginning of the Rx drug epidemic.

  • I would say that my comment was a bit harsh, and that the truth lies somewhere in between.

    Senior officials at the CDC have decided to make the “prescription drug abuse epidemic” a frontline issue, and they have issued many reports with graphs showing the explosion in Rx drug deaths between 2000 and 2012. What these graphs don’t show is that heroin overdose deaths were exploding from 1980 to 1999, and that the growth in heroin overdoses ground to a halt with the advent of the era of prescription drug abuse. With the passage of increasingly strict laws to control Rx drug abuse, we’ve seen growth in prescription drug overdose deathsn grind to a halt fom 2012 to 2014. This halt has been accompanied by a doubling in heroin overdose deaths over just 2 years.

    In the parlance of economists, heroin and prescription painkillers are clearly “interchangable goods” to those who use them recreationally or to satisfy an addiction. Unfortunately they are not to those seeking legitimate treatment of pain, and draconian efforts to restrict addicts primarily end up affecting those who seek to use opiates for their legitimate medical purpose.

    After 40 years of the War on Drugs, the price of a hit of heroin on the streets of San Diego is about $5. I don’t mean any disrespect here for your article, knowledge, or experience, but to me it seems that supply-side efforts to control illicit drug use are a proven failure. Demand will always be met when there is money to be made, and the demand ultimately arises from the injustice and hopelessness that many in our society face on a daily basis.

    I have no doubt that some of the cases of addiction and overdose death are arising from people who initially started using these drugs for their medically appropriate purpose. But if I’m in severe, life-altering pain on a daily basis, I think I have the right to choose whether to take that risk myself rather than having the decision made for me by some paternalistic government agency. If I get dependent, I’ll seek help. And I especially don’t think my choice should be limited because of statistics that conflate addiction that started out with appropriate pain treatment with that which started out with deliberate abuse for recreational purposes.

    The whole supply side approach to drug abuse just doesn’t seem to work.

  • I wouldn’t trivialize the importance of treating pain.

    There is an important difference between pain patients and drug addicts. The pain patients for the most part are not actively complicit in their condition. By comparison, almost everyone who is addicted to a prescription painkiller made the choice at some point either to lie to their doctor about having lost their prescription, to go “doctor shopping” to gain multiple prescriptions, or to purchase drugs illicitly on the street rather than seek treatment for their dependence.

  • “Actually, from a truly scientific viewpoint, this statement is not correct. For a real scientists (and I do acknowledge that most psychiatrists don’t come anywhere close to fitting that description), the assumption would be that the drug DOES cause the reaction that occurs after its administration until proven otherwise.”

    Not even close. You certainly would not agree that any patient with severe depression who remitted after being given a drug remitted because they received the drug. You would look at the difference between drug-treated and placebo-treated patients in a randomized clinical trial.

    As it turns out that specific information is available from the Prozac label. “In US placebo-controlled clinical trials for Major Depressive Disorder, mania/hypomania was reported in 0.1% of
    patients treated with PROZAC and 0.1% of patients treated with placebo”

  • Did anyone on this thread, including Mr. Wipond, actually read the paper criticized by Healy, or are these attacks on the authors’ integrity based solely on what Healy’s second hand account of what it says?

    Per Wipond in the article immediately above, “The NIMH-led study authors stated, though, that there were no significant differences in the rates of these suicidal events for youth taking either the antidepressant fluoxetine (Prozac) or placebo”

    The article he is discussing, however, explicitly states “During the 36-week TADS treatment, 9.8% of the patients randomized to active treatment presented with a suicidal event. The rate was higher (p<0.05) in the fluoxetine (14.7%) than in the psychotherapy group (6.3%),"

    Furthermore, Healy's criticism that the figure in the article misrepresents the fact that most of those who had suicidal events were on Prozac at the time is similarly misfounded. In the paper he criticizes, this figure is immediately followed in the text by the sentence "Some patients who had been randomized to CBT (N=2) or PBO (N=9) and had a suicidal event were in fact on SSRI medication ".

    The abstract of a previous paper by the same authors about the same study states "Suicidal events were more common in patients receiving fluoxetine therapy (14.7%) than combination therapy (8.4%) or CBT (6.3%)."

    So please in the future, it might be a good idea to actually read the paper before attacking the author's character, suggesting they have done something shameful, or belong in prison. The shameful behavior is not on the part of the authors, but by those who attack their character without actually reading what they wrote.

  • I don’t think it’s in any way “utopian” to say that we should look at the data with an open mind and not twist it to make it support our pre-existing beliefs. Nor do I in any way understand your accusation that by opposing misrepresenting the facts I am attempting to “prevent the truth”. Are you arguing that such misrepresentation makes the truth more apparent? Sounds prety Orwellian to me.

    The best and most widely cited evidence tying antidepressants to increased suicide rates comes from an FDA meta analysis of data from manufacturer clinical trials. That data forms the basis of the current warning on the FDA label for all antidepressants, while the small and underpowered study criticized in the Healhy paper barely shows up on the radar as part of the evidence base. Attacking it does not really accomplish anything but allow the authors to publish a paper with a highly provocative title in a minor journal, hoping that it will nonetheless be picked up by blogs such as this one. It really doesn’t add to the scientific discussion in any way, but I guess they accomplished their goal.

  • This was quite an interesting article, and not being familiar with this area, I was surprised at the extent to which much of the data supporting maintenance treatment in bipolar disorder can be explained away as a rebound effect.

    Nonetheless, a few points of concern:

    1) I was surprised to see Jamie Lowe’s description of her positive personal experience dismissed by reference to theory and clinical trial results on this site, where positive clinical trial data is so frequently dismissed by referral to patient anecdotes. What is our standard of proof here? Individual patient anecdotes, randomized clinical trials, or whichever happens to make psychopharmacological approaches looks worse in any given situation?

    2) “It has proved impossible to demonstrate that people receiving modern drug treatment for manic depression do any better than those who don’t, or didn’t.” I would say that problems with design issues and failing to properly consider the possibility of withdrawal phenomena does not show that “it has been impossible to demonstrate” better results, merely that it has not necessarily been done.

    For example, PMID 2237512 describes a trial in which people stabilized on paliperidone were randomized to continue paliperidone or switch to placebo. The median time to relapse was 283 days in the placebo group and 558 days in the paliperidone group. 283 days hardly seems attributable to a rebound effect.

    3) In pointing out the 40% relapse rate at 6 years in patients “known to be compliant” with lithium therapy in reference 15, Dr. Moncrieff fails to mention the study’s conclusions that ” Lithium carbonate was significantly more effective than placebo in preventing relapses” over this time frame.

  • Well, I’m going to stick with my position that a lie is a lie, and that lies that support one’s pre-existing point of view are no bettter than those that support positions one disagrees with.

    Ultimately, the Truth is not served by lies, ever. Deaths caused by overstating the risks of drugs and understating their benefit do not offset those caused by pharma company overpromotion, they just add to them.

  • I agree its generally a mess, but am not sure that the attempt to torture this data to make it confess a negative outcome is any less blameworthy than the attempt to torture it into confessing a positive outcome.

    What I think is important is to look at and evaluate data with an open mind to see what it is telling us, or even to see if it is telling us anything at all. There are too many people out there who simply see it as a polemic tool to twist in whatever way is necessary to argue their pre-existing positions.

  • Both the analysis and Healy’s are pretty much bullshit due to the loss of randomization that occurred from treatment reassignments.

    During the first 12 weeks, 9 participants from the PBO group were moved into the fluoxetine group and 2 from the cognitive therapy group were moved into the the combination therapy group because they were doing especially poorly. This leaves behind only those who are doing relatively well in the non-fluoxetine treatment groups, while adding those with especially severe depression to the drug treatment groups.

    At the end of 12 weeks, only those who were regards as “responders or partial responders” to their assigned treatment were kept in the trial, while those with a poor response were removed and “treated as medically indicated”, but their data continued to be collected. What a mess!

    Given the very high number of non-responders moved from the placebo arm to the fluoxetine group, nothing meaningful can be said about either group. The comparison betwen the first 12 weeks of the combination therapy group and the first 12 weeks of the cognitive therapy only group is somewhat better due to fewer subjects crossing over. In this comparison we find essentially identical suicidal behavior rates between drug treated and non-drug treated persons.

    Rigorous statistical analysis requires thinking about the issues and not just blindly applying formulas. Neither Healy nor the original authors appear to have done the former.

  • No it’s not “ok for our culture to have evolved into dog eat dog”, just as its not OK to twist other people’s words.

    Society has always been unjust. We make a few steps forward, and sometimes we back up. Telling people that their problems are due to injustice is like telling someone whose house is on fire that heavy rain is expected tomorrow morning. It’s true, but its not going to do them a lot of good. They have to learn how to deal with what is, and not simply to point out how it could be better.

  • There is an old joke about an airliner that loses its navigational aids while flying into Seattle. The pilot circles downtown, and seeing a man on the roof of a building, shouts “where am I?” The man shouts back, “you’re in an airplane”. The pilot then circles left, finds the airport, and lands the plane. The copilot asks, “how did you find the airport?” The pilot answers, “the man on the building gave me an answer that was perfectly true but of no practical help whatsoever. I figured it must be the Microsoft building, and I knew that Microsoft is due north of the airport”

    Similarly, pointing to the injustices of society is completely correct, but in the short run, offers little more practical utility than the advice of the man on the roof. Society is unjust, but some are better able to find their way in that unjust society than others. Its not as simple as blaming the problem on society or on the individual, because financial security comes at the interface between the two.

  • The study contradicts the results of a higher quality study (a meta analysis of randomized clinical trial results) conducted by the FDA in a broad patient population without offering any suggestion as to why results in pregnant women should differ from those obtained in the population generally.

    As such, the simplest explanation is that this study is wrong. The potential for confounding in a retrospective cohort study of this type is quite high, and I’m not sure why anyone would bother to perform a study of this type when results from randomized clinical trials are available.

  • Dr. Healy make some interesting points here, but the logical flow of the argument fails in several spots due to misinterpretation and/or highly selective quotation of the literature.

    The claim that the risk of suicide from mild depression is nil is taken from Healy’s own paper, and is in conflict with other, better designed studies. The conclusions of the Healy paper are confounded by the fact that his study was performed on an English population, using psychiatric prevalence rates from the United States, a country with a suicide rate that is double that of the United Kingdom.

    The article further states that the GSK study found that ” these drugs appear to make someone more likely rather than less likely to “act out” if they have just had a partner break up with them.”. What the GSK paper actually says is that people taking antidepressants are more likely to act out in a stressful situation than in the absence of such a situation. Its a very different statement than the one presented above.

    Finally, the article takes it as a given that Lubitz was somehow overcome by the antidepressant that he took, and forced to fly his plane into the ground. There is no evidence for this. According to and FDA meta analysis, NNH for suicidal behavior in this age group was 333, with a relative risk of 2. By comparison, according to UN statistics, as a German male Lubitz represented a risk 5.5-fold greater than a British female. If the pharmaceutical industry has “to put in place systems to manage these risks or to dismantle the system that gives rise to risks like this at a much greater rate than we should have to tolerate.”, then surely the airlines are much to be blamed for subjecting us to the irrational and unpredictable behavior of Continental male pilots.

    Truth comes when we treat the data with respect and an open mind. When we approach it looking only for confirmation of what we already believe, we miss the opportunity for understanding.

  • “Doctors make a living out of the work done by the rest of the population – swallowing pills. These doctors are highly unlikely to confront Andrew Witty or any of the big beasts of the pharmacockracy – unless some of them do so as shareholders”

    I’m not sure I follow. In my last 10 encounters with the healthcare system:

    1. I received a generic cough suppressant for a particularly nasty flu-associate cough.
    2. My PSA was checked. Had it been sufficiently high, it would have been followed up with a biopsy.
    3. I was recommended physical therapy for a frozen shoulder
    4. I underwent colonoscopy as part of routine colon cancer screening
    5. My eyes were checked as part of glaucoma screening. Had the test come back positive, I likely would have been prescribed a generic drug such as a carbonic anhydrase inhibitor
    6. I had a pre-cancerous area removed from the skin of my left cheek

    I can’t actually remember the last time I was prescribed a drug that wasn’t manufactured by an Indian generics company and sold to me for pennies a pill. Overall, in the U.S., which has unregulated drug prices, pharmaceuticals are 9% of national healthcare expenditures.

    So its fine to have a beef with the pharmaceutical industry. But its extraordinary hyperbole to describe the healthcare system as “Doctors make a living by watching patients take pills” or to suggest that clinical trial participants are “serfs”. Unlike serfs, no one is conscripted to participate in a trial against their will, and multiple studies have shown that most participate in hopes of personal benefit.

    A few good points here, but hard to find among the breathless hyperbole.

  • I agree that the use of any pharmacologically active substance during pregnancy is a decision not to be taken lightly. But the article overstated the evidence base and suggests in some cases that speculative harms are widely accepted as proven.

    “Chemical” is a scary word to many people, who fail to realize that 95% of their total exposure to toxic substances comes from natural sources. Peanuts contain aflatoxin, beer contains carcinogenic methyl carbamate as a natural product of fermentation, and tomatos contain methanol which is metabolized to carcinogenic formaldehyde. While maintaining proper vigilance against drug side effects and toxic exposures, its good to also reflect that the dawning of the chemical age has been associated with a decline in childhood mortality from 30% to a fraction of 1%, and increased life exectancy of some 30 years.