A recent meta-analysis of the most commonly prescribed antidepressant drugs raises some very important questions for science-based medicine. The study: Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration, was conducted by Irving Kirsch and colleagues, who reviewed clinical trials of six antidepressants (fluoxetine, venlafaxine, nefazodone, paroxetine, sertraline, and citalopram). They looked at all studies submitted to the FDA prior to approval, whether published or unpublished. They found:
Drug–placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication.
The press has largely reported this study as showing that “antidepressants don’t work” but the full story is more complex. This analysis certainly has important implications for how we should view the body of evidence for these antidepressants. It also illuminates the possible role of publication bias in the body of scientific literature – something that has far ranging implications for science-based medicine.
One of the most successful propaganda campaigns within health care in the last few decades has been the re-branding of nutrition as “alternative” or out of the mainstream of scientific medicine. I have marveled at how successful this campaign has been, despite all the historical evidence to the contrary. I suppose this is partly a manifestation of the public’s short-term memory, but it also seems to reflect basic psychology.
There is evidence that most ancient cultures recognized the importance of diet in health. The Greeks recognized both the benefits of a varied diet and the negative health consequences of obesity, for example. But knowledge of nutrition was limited to these broad observations and was mixed with superstition and cultural beliefs.
The science of nutrition probably dates back to 1614 when scurvy (the disease that results from vitamin C deficiency) was first recognized as a dietary deficiency, one that could be cured by eating fresh fruits and vegetables. In 1747 Lind conducted what might be the first clinical trial – systematically comparing various diets for the treatment of scurvy and finding that citrus fruits were the key to treatment.
South Africa’s Health Minister, Manto Tshabalala-Msimang, is fighting to protect the traditional healers of her country from having their methods tested scientifically. She warns that, “We cannot use Western models of protocols for research and development,” and that she does not want the incorporation of traditional healing to get “bogged down in clinical trials.” Her arguments are anti-scientific and represent a health tragedy for South Africa. However, such attitudes are not uncommon within the community of sectarian medicine and represent some of the common rhetoric used to disguise anti-scientific positions.
This is also not the first controversial statement made by South Africa’s health minister. In 2006 she advocated using garlic and beetroot to treat HIV infection, prompting outrage from South Africa’s academic community. In response to criticism about delays and funding cuts in providing anti-retroviral drugs to HIV sufferers in South Africa, the Health Minister said, “Garlic is absolutely critical, we need to do research on it. We cannot just ridicule it.” South Africa’s president, Thabo Mbeki, resisted calls for Ms. Tshabalala-Msimang’s resignation.
The Food and Drug Administration (FDA) is proposing a very interesting loosening of their regulations of pharmaceutical company marketing. The pros and cons of the proposed changes present an interesting dilemma, with legitimate points on both sides.
When the FDA approves a drug it is approved for a very specific medical indication. I have long thought that FDA approved indications for drugs were too narrow and restricting. For example, most anti-seizure medications are initially approved not for seizures but only for certain types of seizures – for example for adjunctive therapy (meaning it is meant to be added to another drug rather than used alone) for focal onset seizures (and not against primary generalized seizures – or ones that begin all over the brain at once).
Once approved physicians are free to use drugs as they see fit. If evidence shows that a new seizure medication is effective as first line treatment, then it is ethical good medicine to use it that way, even if it is not FDA approved for that use (this is called off-label use). FDA approved is not equivalent to science-based.
The core principle of science-based medicine is that health care decisions should be based upon our best current scientific evidence and understanding. When applied to the regulation of health products this means that health claims should first be required to meet some reasonable threshold of scientific evidence before they are allowed. Admittedly this is not a purely scientific question but the application of scientific knowledge to an essentially political question – the balance of protection vs freedom.
Regardless of where one thinks this balance should be, I think most would agree that is it a problem if the public generally wants more protection than it is getting, or believes it is currently getting more protection than it is. A Harris poll from 2002 indicates that the majority of Americans believe that companies cannot make health claims about supplements unless they have been proven scientifically and approved by the FDA, when in fact this is not the case. The Dietary Supplement Health and Education Act of 1994 (DSHEA), largely through the efforts of Senator Orin Hatch from Utah, removed supplements from the control of the FDA and specifically allowed for so-called structure function claims to be made about products without any burden of proof. Most Americans are not aware of this fact.
A new study by lead author Shelly Gray and published in the latest issue of the Journal for the American Geriatric Society, found no effect from taking Vitamin C or E, either alone or in combination, on the risk of dementia or Alzheimer’s disease after 5.5 years. Vitamins C and E were chosen because they both have significant antioxidant activity, and so this study was partly to test the hypothesis that oxidative stress causes or contributes to dementia.
The science behind the role of oxidative stress in aging and neurodegenerative disorders and the modulation of oxidative stress by nutritional antioxidants is complex and has not yielded many confident therapeutic recommendations. And yet, by contrast, antioxidants are sold to the public with dramatic health claims as if they were well established. It is common for marketing hype to out pace scientific reality, especially when the science is complex and preliminary so that there is as yet no firm scientific consensus.
For background, oxidative stress refers to the production in the cells of the body of certain oxygen-based compounds, collectively called reactive oxygen species (ROS), that are highly reactive. Some of these compounds are simply waste products of cell metabolism. Others serve a useful purpose, such as nitric oxide that is used in neurotransmission. What these ROS compounds have in common is that they react with proteins, DNA, and other cell components and cause damage.
While attending a lecture by a naturopath at my institution I had the opportunity to ask the following question: given the extreme scientific implausibility of homeopathy, and the overall negative clinical evidence, why do you continue to prescribe homeopathic remedies? The answer, as much as my question, exposed a core difference between scientific and sectarian health care providers. She said, “Because I have seen it work in my practice.”
There it is. She and many other practitioners of dubious modalities are compelled by anecdotal experience while I am not.
An anecdote is a story – in the context of medicine it often relates to an individual’s experience with their disease or symptoms and their efforts to treat it. People generally find anecdotes highly compelling, while scientists are deeply suspicious of anecdotes. We are fond of saying that the plural of anecdote is anecdotes, not data. Why is this?
A recent study published in the Journal of General Internal Medicine and featured in a Time Magazine article, indicated that of 466 academic physicians in the Chicago area, 45% indicated that they have prescribed a placebo for a patient. This has sparked a discussion of the ethics of prescribing placebos in particular and deception in general in medicine.
A placebo is a biologically inactive treatment, such as a sugar pill. Any perceived benefit from taking a placebo is due to a combination of factors, mostly biased observation and non-specific effects, collectively referred to as the placebo effect. I discussed the placebo effect at length last week, and now will delve deeper into the question of deception in medicine more generally.
Prior to about 30 years ago the relationship between a physician and their patient was functionally paternalistic. This means that the physician did what they thought was best for their patients as a parent would for their child. It also meant that “benign deception” was often used, including prescribing treatments that were known to be inactive or ineffective. Sometimes the deception was one of omission – for example, not telling a patient that their disease was terminal and incurable so as not to upset them needlessly.
Recently the Federal Trade Commission went after the makers of the Q-Ray Ionized Bracelet for their claims that their device was a cure for chronic pain. Last week Seventh Circuit judge Frank Easterbrook handed down his opinion on the company’s appeal, writing that the company was guilty of fraud and ordering them to pay 16 million dollars in fines. One of the key points for the company’s defense was that the Q-Ray Ionized Bracelet is legit because it exhibits the placebo effect. Judge Easterbrook was not impressed with this argument, writing:
“Like a sugar pill it alleviates symptoms even though there is no apparent medical reason. Since the placebo effect can be obtained from sugar pills, charging $200 for a device that is represented as a miracle cure but works no better than a dummy pill is a form of fraud.”
This decision creates an interesting precedent, since there are a large number of fanciful treatments that do not have any “apparent medical” mechanism and that are claimed by its proponents to work through a placebo effect. In my experience the placebo effect, briefly defined as a measurable response to an inert treatment, is almost completely misunderstood by the public – a fact that is exploited by purveyors of dubious treatments such as the Q-ray. Already in the comments of this blog there has been discussion over the nature of the placebo effect.
Belief in the healing power of magnets and magnetic fields has existed since the discovery of magnets several thousand years ago. In the late 18th century, Franz Anton Mesmer, an infamous charlatan, promoted the notion that he could heal with “animal magnetism.” In the 19th century magnetic healers were common – D.D. Palmer was a magnetic healer prior to founding chiropractic. Magnetic devices for everyday aches and pains have been increasingly popular recently, and today they are a multi-billion dollar industry.
Yet the scientific evidence does not, generally, support the use of magnets for specific indications, and the vast majority (if not totality) of claims made for magnetic devices in marketing are either false or unsupported and highly implausible. The media attention given to a recent study of static magnetic fields (SMF) in the treatment of inflammation brings up many important points regarding this disconnect.
A sciencedaily.com headline from January 7th proclaims: “Healing Value Of Magnets Demonstrated In Biomedical Engineering Study.” This headline is extremely misleading, especially the use of the word “healing.” The article is referring to a study by CE Morris and Thomas Skalak(1) published two months ago in the American Journal of Physiology – Acute Exposure to a Moderate Strength Magnetic Field Reduces Edema Formation in Rats. In the sciencedaily article Skalak is quoted as saying:
“We now hope to implement a series of steps, including private investment partners and eventually a major corporate partner, to realize these very widespread applications that will make a positive difference for human health.”
This optimism, however, is premature, and represents a significant problem with many popular therapies, the extrapolation from preliminary pre-clinical studies to clinical applications in humans. But before I look at this new study in more detail I will review some basic concepts for background.