Do antidepressants work?
If you read the studies submitted by Pharma to the FDA, but never published, the answer is no.
If you read the published studies, the answer is yes.
As I reviewed extensively in HOOKED, it is old news that papers published in medical journals, of research funded by industry, disproportionately favor the company's drug; and that research studies showing the drug in a bad light have routinely been suppressed. What's newsworthy about the paper by Erick Turner and colleagues in the January 17 New England Journal is the breathtaking extent of the resulting bias.
The group had access to the FDA reviews of 74 company-sponsored studies of 12 different antidepressants. The data showed whether the study was viewed as positive or negative in terms of the drug's superiority to placebo; and the size of the positive effect if there was one. They then tracked down whether each study was eventually published in a journal, and whether one reading the article would classify the study as positive or negative.
Of 38 studies deemed positive by the FDA reviewers, 37 were published. Of 36 studies deemed to be negative or questionable, 22 were not published at all, and 11 were published with an interpretation that made them sound positive, so that the true negative outcome was concealed in one way or other in 33/36 studies.
There was also the interesting mystery of the effect size. The effect size reported in the published papers (which, remember, were virtually all positive) exceeded the effect size calculated by the FDA reviewers by an amount ranging from 11 to 69 percent. The median increase in effect size was 32 percent, meaning that on average, published papers made the drugs sound one-third more effective than the scientific data (at least according to the FDA) would support.
In other words, if we assumed that an evil demon was at work, trying to make it impossible for the readers of medical journals to know the truth about antidepressant efficacy, we would expect results precisely matching those actually uncovered by Turner et al.
So, can we give this evil demon a name? Turner et al. demur. They have no way of knowing whether all these papers were submitted to journals, and were turned down by editors because they were negative, and who wants to read a boring ol' negative study; or whether the drug company never submitted the papers for publication, or some of each.
Now, a couple of comments at this point. First, it seems that once we have identified this set of 74 studies, we have an extremely useful database for further inquiry. On patient investigation, it ought to be quite possible to determine the submission-to-journals track record (or lack of same) for each of the 74 studies (or rather, the 23 that were not published according to Turner and company). Since Congress is starting to interest itself in these matters, including such arcane issues as Robert Jarvik's qualifications to shill for Lipitor on TV, it's even conceivable that if all else fails, the 23 PI's of those studies could be subpoenaed to Capitol Hill to testify under oath. Then we would know a lot more.
Next comment--if a paper is not published, it may be the drug company not submitting it, or it may be the editor rejecting it. But if the paper is published, and the effect size has magically grown like Pinocchio's nose, can we really suspect that perhaps the editor personally rewrote the manuscript and made the company's drug sound better than it is? Or do we have to suspect the drug company in-house statisticians of doctoring the manuscript? To me, the company is much more likely to be the culprit. And, while awaiting further evidence, if the company is the culprit in that part of this intrigue, I have to be suspicious that non-submission to journals can be laid at that doorstep also.
Having said that, I still must admit that journal editors have not in the past acted in a way that would make them seem blameless in all this. In both the VIGOR and CLASS trials, as related in HOOKED, we have some strongly suggestive evidence that the editors of major journals (NEJM and JAMA) colluded with the academic authors of drug company sponsored trials, to make the results sound better and the risks sound less than they really were. Richard Smith, former BMJ editor, has written about the millions of dollars major journals can make when drug companies buy up reprints of highly successful clinical trials. So we need to keep in mind the possibility of collusion in the antidepressant trials as well.
Meanwhile, I have another question. One of my jobs is teaching medical students. Up till now, I have always taught them that a good doctor carefully reads the medical journals and decides how to treat patients based on what we read there. How can I go on telling them this, with a straight face?
Turner EH, Matthews AM, Linardatos E, et al. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 358:252-260, 2008.
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Current Depression Medications: Do The Benefits Outweigh the Harm?
Presently, for the treatment of depression and other what some claim are mental disorders, as they are questionable, selective serotonin reuptake inhibitors are the drugs of choice by most prescribers. Such meds, meds that affect the mind, are called psychotropic medications. SSRIs also include a few meds in this class with the addition of a norepinephrine uptake inhibitor added to the SSRI, and these are referred to SNRI medications. Examples of SNRIs are Cymbalta and Effexor. Some consider these classes of meds a next generation after benzodiazepines, as there are similarities regarding their intake by others, yet the mechanisms of action are clearly different, but not their continued use and popularity by others.
Some Definitions:
Serotonin is a neurotransmitter thought to be associated with mood. The hypothesis was first suggested in the mid 1960s that this neurotransmitter may play a role in moods and emotions in humans. Yet to this day, the serotonin correlation with such behavioral and mental conditions is only theoretical. In fact, the psychiatrist’s bible, which is the DSM, states that the definite etiology of depression remains a mystery and is unknown. So a chemical imbalance in the brain is not proven to be the cause of mood disorders, it is only suspected with limited scientific evidence. In fact, diagnosing diseases such as depression is based on subjective assessment only, as interpreted by the prescriber, so one could question the accuracy of such diagnoses.
Norepinephrine is a stress hormone, which many believe help those who have such mood disorders as depression. Basically, with the theory that by adding this hormone, the SSRI will be more efficacious for a patient prescribed such a med.
And depression is only one of those mood disorders that may exist, yet possibly the most devastating one. An accurate diagnosis of these mood conditions lack complete accuracy, as they can only be defined conceptually, so the diagnosis is dependent on subjective criteria, such as questionnaires. There is no objective diagnostic testing for depression. Yet the diagnosis of depression in patients has increased quite a bit over the decades. Also, few would argue that depression does not exist in other people. Yet, one may contemplate, actually how many other people are really depressed?
Several decades ago, less than 1 percent of the U.S. populations were thought to have depression. Today, it is believed that about 10 percent of the populations have depression at some time in their lives. Why this great increase in the growth of this condition remains unknown and is subject to speculation. What is known is that the psychiatry specialty is the one specialty most paid to by certain pharmaceutical companies for ultimately and eventual support of their psychotropic meds, as this industry clearly desires market growth of these products. Regardless, SSRIs and SRNIs are the preferred treatment methods if depression or other mood disorders are suspected by a health care provider. Yet these meds discussed clearly are not the only treatments, medicinally or otherwise, for depression and other related disease states.
Over 30 million scripts of these types of meds are written annually, and the franchise is around 20 billion dollars a year, with some of the meds costing over 3 dollars per tablet. There are about ten different SSRI/SRNI meds available, many of which are now generic, yet essentially, they appear to be similar in regards to their efficacy and adverse events. The newest one, a SNRI called Pristiq, was approved in 2008, and is believed to being promoted for treatment for menopause. The first one of these SSRI meds was Prozac, which was available in 1988, and the drug was greatly praised for its ability to transform the lives of those who consumed this medication in the years that followed. Some termed Prozac, ‘the happy pill’. In addition, as the years went by and more drugs in this class became available, Prozac was the one of preference for many doctors for children. A favorable book was published specifically regarding this medication soon after it became so popular with others.
Furthermore, these meds have received additional indications besides depression for some really questionable conditions, such as social phobia and premenstrual syndrome. With the latter, I find it hard to believe that a natural female experience can be considered a treatable disease. Social phobia is a personality trait, in my opinion, which has been called shyness or perhaps a term coined by Dr. Carl Jung, which is introversion, so this probably should not be labeled a treatable disease as well. There are other indications for certain behavioral manifestations as well with the different SSRIs or SRNIs. So the market continues to grow with these meds. Yet, it is believed that these meds are effective in only about half of those who take them, so they are not going to be beneficial for those suspected of having certain medical illnesses treated by such meds. The makers of such meds seemed to have created such conditions besides depression for additional utilization of these types of medications, and are active and have been active in forming symbiotic relationships with related disease- specific support groups, such as providing financial support for screenings for the indicated conditions of their meds- screening of children and adolescents in particular, I understand, and as a layperson, I consider such activities dangerous and inappropriate for several reasons.
Danger and concerns by others primarily involves the adverse effects associated with these types of meds, which include suicidal thoughts and actions, violence, including acts of homicide, and aggression, among others, and the makers of such drugs are suspected to have known about these effects and did not share them with the public in a timely and critical manner. While most SSRIs and SNRIs are approved for use in adults only, prescribing these meds to children and adolescents has drawn the most attention and debate with others, such as those in the medical profession as well as citizen watchdog groups. The reasons for this attention are due to the potential off-label use of these meds in this population, yet what may be most shocking is the fact that some of the makers of these meds did not release clinical study information about the risks of suicide as well as the other adverse events related to such populations, including the decreased efficacy of SSRIs in general, which is believed to be less than 10 percent more effective than a placebo. Paxil caught the attention of the government regarding this issue of data suppression some time ago, this hiding such important information- Elliot Spitzer specifically, as I recall.
And there are very serious questions about the use of SSRIs in children and adolescents regarding the effects of these meds on them. For example, do the SSRIs correct or create brain states considered not within normal limits, which in effect could cause harm rather than benefit? Are adolescents really depressed, or just experiencing what was once considered normal teenage angst? Do SSRIs have an effect on the brain development and their identity of such young people? Do adolescents in particular become dangerous or bizarre due to SSRIs interfering with the myelination occurring in their still developing brains? No one seems to know the correct answer to such questions, yet the danger associated with the use of SSRIs does in fact exist. It is observed in some who take such meds, but not all who take these meds. Yet health care providers possibly should be much more aware of these possibilities
Finally, if SSRIs are discontinued, immediately in particular instead of a gradual discontinuation, withdrawals are believed to be quite brutal, and may be a catalyst for suicide in itself, as not only are these meds habit forming, but discontinuing these meds, I understand, leaves the brain in a state of neurochemical instability, as the neurons are recalibrating upon discontinuation of the SSRI that altered the brain of the consumer of this type of med. This occurs to some degree with any psychotropic med, yet the withdrawals can reach a state of danger for the victim in some classes of meds such as SSRIs, it is believed.
SSRIs and SRNIs have been claimed by doctors and patients to be extremely beneficial for the patient’s well -being regarding the patient’s mental issues where these types of meds are used, yet the risk factors associated with this class of medications may outweigh any perceived benefit for the patient taking such a drug. Considering the lack of efficacy that has been demonstrated objectively, along with the deadly adverse events with these meds only recently brought to the attention of others, other treatment options should probably be considered, but that is up to the discretion of the prescriber.
“I use to care, but now I take a pill for that.” --- Author unknown
Dan Abshear
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