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It's been many years since I have trusted anything I read in a medical or psychiatric journal. There is an enterprise-wide positive bias; findings never seem to replicate; benefits are hyped; harms are hidden.

Drug companies bear most of the blame- the research they sponsor is shoddy and market driven. Scientists are also to blame when they torture data so much it will confess to anything. Medical journals are to blame when they publish positive findings from lousy studies and reject negative results from well done studies, and journalists are to blame when they uncritically accept phoney claims. It won't surprise you that the most widely cited study in the recent literature is also my favorite: 'Why Most Published Research Findings Are False' by John Ioannidis.

David Healy MD has been a leader in exposing the harms of drug treatments and the tricks of drug companies. He has also attacked the accepted wisdom that evidence based medicine requires the foundation of randomized, placebo controlled clinical trials (RCT). I agree with much of his criticism, but not with his conclusions. Here is a brief synopsis of our debate.

Dr Healy writes: "Most papers reporting results of drug sponsored randomized clinical trials are ghostwritten by people hired by the drug company. In a world where we usually have no access to the raw data, such papers published in premier medical journals can claim as safe and effective a drug that is in fact dangerous and ineffective. This is bad medical research that leads to bad medical practice.

"Proponents of Evidence Based Medicine (EBM) agree that drug company research behaviour is egregiously bad, but argue this does not necessarily prove that clinical trials are inherently flawed. The problem supposedly lies in letting industry design, conduct, and implement the trials. Presumably everything would be okay if only the trials were designed and run by Angels or the Government - studies would then deliver trustworthy, gold standard evidence that cannot possibly be obtained in any other way. EBM proponents favor the presumed objective results of controlled RCT's to the subjectivity of uncontrolled clinical observation. Without RCT's, they claim, we cannot practice Evidence Based Medicine.

"Should industry be stripped of the right to ghostwrite trials and be forced to allow access to the trial data they don't own? Sure, but even if run by Angels, trials favour industry because they allow weaker and weaker drugs to enter the market, while hiding the harms.

"Here's how. Clinical trials began as a way to demonstrate that experimenters knew what they were doing. If on the basis of good laboratory science demonstrating the pathology of a condition or direct observation of cures we had a drug that corrected a problem, then comparing it to placebo randomly allocated would show the drug to be superior to placebo. This test would not lead to new knowledge - it would confirm what we think we already know.

"The only time we learn something from clinical trials is when a huckster who has duped vulnerable patients into taking a drug for some purpose is forced to compare his nostrum to placebo and the trial shows him to be a conman. A demonstration like this can make a major contribution to patient safety.

"In 1962, following the thalidomide crisis and just after the RCT method was developed, there was a political imperative to improve the safety of drugs. Based on the possibility that controlled study might control hucksterism, RCTs got built into the regulatory apparatus. It seemed a good idea to force the pharma camel to pass through the eye of a scientific needle in order to protect vulnerable patients. No-one recognized the pitfalls.

"First, in trials we compare a drug to placebo. Even snake oil would come out as having a benefit if we put a large enough number into the trial.Second, to run an RCT you have to hypnotize investigators and patients to ignore the 99 things a drug does, and focus instead only on one thing - the thing both pharma or some Angels want you to focus on. There is a risk in generating ignorance in this way in order to nail down one effect while having a kind of hysterical blindness to harms. It's worth taking the risk when we show the drug doesn't work and the drug doesn't then get on the market - which is what people expected in 1962, but is not what has happened since. Third, RCTs are supposed to deliver objectivity by controlling confounders but when both the illness and the drug produce the same symptom, RCTs create ineradicable confounding. They make it possible for drug companies or Angels to pass off the harms caused by treatment as a symptom of the illness being treated. And in medicine, it's very common for both an illness and its treatment to produce overlapping effects.

"To then claim, as the rhetoric of Evidence Based Medicine does, that RCTs provide gold standard knowledge about what drugs do is to generate ignorance about ignorance.

"This is not just an abstract ignorance. In 1962, it took a year or two from the time of a drug's launch to recognize its major hazards. It now takes decades from the time of first description to the point where the field accepts a link between treatment and hazard.

"Drug induced death is likely now the leading cause of death - it's difficult to be certain because we don't collect the data adequately. And little is being done to remedy our lack of awareness of drug risks.

"More of the same RCTs are not the remedy. The calculations that come out of an RCT are only as good as the data (observations) that go in. In the belief that RCTs are more objective than doctors and patients, we have undermined the abilities of people to observe and act on the basis of their observations. It is when people with a range of biases agree on what they are seeing that we get objectivity - a mechanical process can never deliver this.

"RCTs created Evidence Based Medicine. Most listeners hearing EBM hear Data Based Medicine, but evidence is not data. Statistical calculations derived from aggregates are a way to deal with conmen - not a guide to the practice of medicine. The individual patient is the datum in medicine."

Thanks Dr Healy. I agree with you on the diagnosis of what ails the clinical research literature, but disagree with your suggested cure. If we have learned one thing from the history of medicine it is the dangerous fallibility of uncontrolled and anecdotal clinical observation. Doctors have killed patients for millennia by bleeding them, administering emetics and cathartics, and prescribing poisons. The power of the placebo effect, the vagaries of chance correlational associations, and observer bias all overwhelm the generalyzability of any given clinical observation.

Dr Healy is right about the fallibility of clinical trials, especially when their basic purpose is not to help patients, but rather to sell drugs or advance research careers, but his solution is even more fallible. We have done the experiment for thousands of years and the clear conclusion is that anecdotal medicine is arbitrary and harmful medicine.

The only responsible courses of action are to improve designs and measures, standardize implementation, change sponsors, achieve complete transparency, report harms as thoroughly as benefits, and eliminate hype. With all the limitations, there is simply no substitute for randomized placebo controlled studies-we must improve them because we can't do without them.

However, it is clearly allowing the fox to guard the henhouse to give drug companies the franchise in conducting the studies that lead to the regulatory approval of their products. The huge financial rewards will inevitably lead to badly biased implementation that cannot be adequately corrected even if there is complete after the fact transparency.

Drug companies should be taxed to support an independent testing agency that would be responsible for conducting consumer oriented clinical trials for safety and efficacy prior to regulatory approval and for collecting later surveillance data on adverse effects. No system will ever be perfect, but independent trials would be a great advance over the junk we have now and far more trustworthy than the uncontrolled clinical observation suggested by Dr Healy.

Dr Healy replies: "It's a mistake to generalize from the effects of a drug on the patient in front of me to the average effects of a drug, but it is an even more dangerous clinical mistake to generalize from average effects in studies to the patient in front of me. The drugs that came on the market in the 1950s before we began using RCTs were more effective and safer - guided by doctors reporting on what they saw in front of them - that the drugs we have had since."

I answered: "The pioneer drugs of the 50's were all such home runs they could be discovered by clinical serendipity and n of 1 observation. But the low hanging fruit has all long since been picked. Refinements with much lower effect sizes require systematic study."

Dr Healy's last word: "Do we want treatments with low effect sizes especially if their hazards are hidden by the trial process?"

My last last word: "We can't expect every useful drug to be a home run."

Doctors prescribe way too many medicines for patients who don't really need them. A lot of the pressure comes from intense drug company marketing. Some comes from patients who aren't happy leaving the office without a pill. And doctors have too little time with each patient to explain non-pill solutions to problems. Wild prescribing is not new. For thousands of years, doctors have given patients useless (and often quite harmful) drugs and patients have taken them.

Modern medicine was meant to be different- it would be based on scientific evidence that could tease out real effect from placebo effect. Unfortunately, evidence-based medicine is only as good as the evidence it is based on. And in many instances our evidence is not very good because it comes from biased drug company studies.

This is particularly true for the 'off-label' prescription of medicines- use based not on the systematic study required for an FDA indication. Off-label prescribing is the wild west of medicine- any doctor can prescribe any drug for any problem.

Kim Witczak became involved as an ardent drug safety advocate after the death of her husband, Tim "Woody" Witczak, in 2003 as a result of a drug side effect that had not been disclosed to him. She has taken her personal experience and launched a national drug safety campaign through www.woodymatters.com:

"Doctors routinely give powerful drugs off-label to their patients, without strong scientific evidence proving the drugs will be safe or effective, and sometimes despite warnings that such prescribing could cause serious harm.

"All the while, patients have no idea that the drug that's being recommended to them does NOT have FDA approval for the particular condition. They just assume and trust their doctor.

"Once a drug has been approved for sale for one purpose, physicians are free to prescribe it for any other purpose. They are not limited to official, FDA-approved indications. Off-label prescription use is very common.  Up to one-fifth of all drugs are prescribed off-label and amongst psychiatric drugs, off-label use rises to 31%.

"A recent study reveals that one third of children in foster care diagnosed with ADHD have been treated off-label with an atypical antipsychotic medication. As a parent, would you consent to your child being prescribed an antipsychotic medication? The name alone should raise a red flag. And most atypical antipsychotics are NOT approved by the FDA for use by children. 

"Drugs are often used off-label, with nearly 80 percent of off-label prescriptions lacking 'strong scientific evidence,' which means we do not know if their risks outweigh their benefits.  Ultimately, its buyer beware.   

"It's one thing if you have a rare disease and are desperate to try something that might offer hope. It's another thing if you went into your doctor because you're having trouble sleeping due to stress of a new job.  Again, it's a fine (yet potentially deadly) line patients are walking.  We need to be told if the FDA has approved the product or if its being used off-label based on an article that appeared in some journal.  Otherwise, we are just guinea pigs.  

"The FDA may soon make matters worse. It is considering new policies on distributing reprints of medical and scientific journal publications. In its new draft guidance entitled, 'Distributing Scientific and Medical Publications on Unapproved New Uses-Recommended Practices.'  The drug industry will be allowed to distribute journal articles and clinical practice guidelines (CPGs) regarding off-label use of their products to the medical community. This is basically a loophole for the pharmaceutical companies to promote their products off-label.  

"In recent years, over $13 billion in fines have been paid by major drug companies to settle lawsuits against them for their fraudulent marketing practices, including off-label promotion of their drugs/devices not approved by the FDA.  

"There's a fine line between the drug company informing doctors about a new potential benefit in an off-label indication and the illegal promotion of product for increasing sales.  

"In my opinion, this new guidance sends mixed messages. On the one hand, the FDA states that it 'recognizes the value to health care professionals of truthful and non-misleading scientific or medical publications on unapproved new uses.'

"But as everyone knows, medical journal articles are often biased because the authors or ghostwriters are paid by the company whose product is being studied.  This should be very concerning to the doctors and patients alike.

Now more than ever, Informed consent is needed. It's a great opportunity for patients and/or their caregivers to have an intentional conversation with their doctor about their medications. Armed with ALL the information, including if the drug is being used off-label, patients are then able to make an educated and informed decision about their drugs.

"It sure seems like we could all get behind this concept and demand informed consent for drugs being given off-label.  It just makes common sense for everyone, patients and doctors, alike."

Thanks, Kim. This is a great suggestion that I would extend even further. Why not require doctors to get written informed consent from their patients for all use of medication? This would make for much better informed consumers and reduce careless over prescription of medication.

Off-label prescribing is much better for drug company profits than for patient welfare. Using medicines for unapproved uses on balance probably does much more harm than good. The doctor has no reason to think the medicine will work, every reason to know it will have side effects. Prescribing for indicated uses is over done, prescribing for off-label use is rarely justified.

It would be a great mistake for the FDA to loosen its already weak control over drug company salesmanship.  Drug companies have in past sustained large fines for illegal off-label marketing because the rewards are so great. FDA would be opening the gates to even more unscrupulous drug marketing. We need to restrict misleading marketing not promote it.

 The argument that drug sales people are educating physicians doesn't pass the laugh test. Their compensation is based on how much product they can move, not on appropriateness of prescription. And no study funded by a drug company can ever be trusted.#

In many previous blogs, I have bemoaned the shameful state of psychiatric care and housing for people with severe mental illness.

My conclusion was that the United States now is the worst place and worst time ever to have a severe mental illness. Hundreds of thousands of the severely ill languish inappropriately in prisons. Additional hundreds of thousands are homeless on the street. 

But it gets worse. Having a severe mental illness also means that you will probably die very young. I have asked Dr Peter Weiden to explain why and to suggest what we should do about it. He is Professor of Psychiatry at University of Illinois Medical Center and has spent his professional career working on improving outcomes and reducing side effects and complications for people with serious mental illness.

Dr Weiden writes: "In the general population, our life expectancy in the United States is approximately 80 years (77.4 years for men, and 82.2 years for women). This is a stunning improvement in life expectancy since back in the 1970's when life expectancies were a full decade shorter, around 70 years. The rapid and profound decrease in smoking is probably the single most important factor.

Certain groups do not share this good fortune. For example, black Americans live about 5 fewer years than whites. But one group suffers by far the most- with an average of 20 years of reduced life, in the ballpark of the life expectancy in Rwanda or Afghanistan.

Who is dying so young? You might think it would be people with HIV or severe asthma or some other serious medical condition. But it is not. As you have guessed by now, the group in question are those with a diagnosis of serious mental illness-schizophrenia, bipolar disorder or treatment resistant depression.

It has been known for many years that individuals with serious mental illness were more likely to have medical problems like diabetes, hypertension, or heart disease, but most of the mortality concern was on suicide prevention and other kinds of injuries that come from poorly controlled psychiatric symptoms.

The wake up call came in 2006 when a groundbreaking study of mortality statistics showed that individuals with severe mental illness were dying between 13 and 31years early, averaging to over 20 years of life lost relative to age matched general populations. Their causes of death were actually very similar to the causes of death in the general population, only happening on average about 20 years earlier.

While suicide and accidental deaths are still much more likely to happen in the severely mentally ill relative to general population, these are still relatively uncommon, whereas there is a doubling or tripling of the mortality from heart disease, diabetes, respiratory ailments, and cancer. People mostly die in their 50s of the same problems that kill off the rest of us 20 years later.

Many reasons conspire to create this shameful statistic. People with severe mental illness are less likely to take good care of themselves, more likely to smoke heavily and have sedentary lifestyles, and have more difficulty than most negotiating the complicated medical care system to go for appointments and follow-up care. And primary care physicians are not well trained or compensated for the additional complexities involved in diagnosing or treating medical problems in the severely ill.

A word about medications for mental illness, and their role in mortality. It is a complicated question because medications can be very effective in controlling psychiatric symptoms so that patients are better able to reduce medical risks and actively participate in medical care. On the other hand, some medications cause significant weight gain and dyslipidemia (increase in triglycerides and cholesterol) which can make the already bad situation worse. This dilemma is better now that there are effective medications that do not often cause weight gain or elevated lipids. Though this remains a vexing challenge for mental health professionals, the major problem seems to be the greater number of medical risk factors among persons with mental illness and their lack of access to high quality medical care.

A growing research literature shows that bringing the medical doctor to the psychiatric patient works much better than trying to bring the patient to regular medical services. The merging of primary psychiatric care with primary medical care is urgently needed.

Is this too much to ask? When we get surgery we expect other doctors to be available. The surgeon will be surrounded by a team including radiologists, anesthetists, and if there are heart problems a cardiologist. Having an appropriate medical team working together is usually not available for those who have psychiatric conditions.

Which throws the basic inequality into stark relief. Society would not tolerate 20 years of lost life expectancy for other groups, even those that also suffer discrimination like Latino or blacks or gays. If this were HIV or breast cancer or multiple sclerosis, we would not tolerate the total fragmentation of healthcare as we do with mental illness.

We are complacent because the lives of those with severe mental illness do not matter to us. Unless the person dying young is your parent or your child, or your brother."

Thanks so much, Peter, for this glum, but much needed assessment. Until recently, I have assumed that the reduced life expectancy in the severely ill was attributable to the big four of lousy medical care, heavy smoking, sedentary lifestyle, and antipsychotic use. To my great surprise, a large and well conducted study recently found the lowest mortality in the severely ill who had received low to moderate doses as compared to those who took no medicine or high doses. This is just one study and can be interpreted in different ways, but it does suggest that antipsychotics are less the culprit in early death than I had imagined.

Which focuses attention even more on lousy medical care, and smoking. Clearly, we must improve not just the current totally inadequate psychiatric care and housing provided for the severely ill, we must also follow Dr Weiden's suggestion that medical care be an essential part of the package- along with smoking cessation and exercise.

Will anything change? The (non)treatment of severe mental illness in the US is our national shame. This is voiceless constituency in the US that very few people seem to care about. It is different in much of Europe where enlightened policies and adequate funding for the severely ill lead to decent lives in the community and better healthcare.

There is media and political outcry when there is poor health care for the military, or children, or women or minorities. everyone went crazy when one person died of Ebola. We should be deeply ashamed of ourselves for neglecting the severely ill- creating a system that imprisons them, renders them homeless, and allows them to die so young. We need a Charles Dickens to illustrate their plight and a new Pinel to free them of their chains. Two centuries ago, the age of enlightenment banished the idea that mental illness was caused by witchcraft or possession. As Harry Stack Sullivan put it- people with schizophrenia were more simply human than otherwise. Its long past time that we remembered this and acted accordingly. #

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