Monday, December 8, 2008

New Study of Publication Bias

Back in January I wrote about a very important study by Turner et al. in NEJM:

Turner and colleagues in Portland showed a truly scary degree of publication bias in journal articles about depression--with roughly half the research studies of SSRI antidepressants showing effectiveness and half not, and with virtually all studies that showed effectiveness getting published, and virtually none of those showing no effectiveness getting published. They managed this study by comparing the FDA biostatisticians' independent review of data presented as part of new drug applications, with the eventual publication that resulted (or failed to result) from the research. They also showed that many published studies were "spun" as positive when they had been assessed by the FDA experts as negative; and that the effect sizes reported in the published studies were frequently inflated from those discerned by the FDA review. The major limitation of Turner et al. was that they addressed only one class of drugs, antidepressants. They also included data that are now many years out of date, perhaps not reflecting more recent practices.

A group at UCSF led by Kristin Rising set out to remedy these deficiencies in a new study:

They looked at all new molecular entities approved by the FDA in the years 2001 and 2002, reasoning that this would have given the investigators enough time to publish all studies that were likely to be published. They reviewed the FDA assessments of all efficacy studies submitted by the drug companies as part of those new drug applications, conducting an extensive search to see if that study was ever published. They also compared the primary endpoints and the conclusions of all FDA-submitted studies with what appeared in the resulting publication (for those studies that were published).

The results were in the same general ballpark as what Turner et al. had found for antidepressants, only not quite so dramatically disastrous. Rising et al. found that 78 percent of the studies they looked at were published. A study submitted to the FDA that showed the company's drug to be effective was about 4 times more likely to be published. Between FDA submission and eventual journal publication, a number of primary trial endpoints that did not show the drug favorably got dropped out, and some new primary endpoints that had not been submitted to the FDA were added, in each case showing the drug in a positive light. The statistical significance of some outcomes changed between FDA submission and publication, in each case in a way that favored the drug.

In sum, Rising et al. noted the same shenanighans--multiple changes being made to the study results by the time they were published, if they were published at all, resulting in a drug footprint in the published literature that bore only a tenuous resemblance to the data submitted to the FDA. The basic lesson is that commercial sponsorship of pharmacotherapy trials has made it harder and harder to practice evidence-based medicine, as the "evidence" is routinely altered in such a way as to make drugs look more effective and safer than they are.

Rising et al. note that a number of the shenanighans they detected could have been prevented by the earlier adoption of mandatory trials registries, aso those who believe that this is the answer to commercial sponsorship will be heartened. I argue in HOOKED that registries are a useful first step but that ultimately a bigger firewall between company money and the conduct of clinical trials is needed.

1 comment:

Anonymous said...

Serotonin Enhancing Psychotropic Pharmaceuticals

In the 1930s, physicians approached the mental illness of depression a bit differently that we do today. While acknowledging a cause of depression is often due to some great misfortune, they seemed to focus on what is called a complex. A complex is disturbances of ideas and impulses that are the cause of consistent habitual patterns of thought, feelings, and behavior. An example of this state of mind of one who is depressed is one who experiences an exaggerated or obsessive concern or fear. And the etiology for this mental disorder was often undefined. In the 1930s, psychotherapy such as cognitive therapy was recommended for treating the depressed patient, and not pharmacological therapy. Also considered for the depressed patient was positive lifestyle changes that would lessen the pain that the depression was causing them.
Times have changed since then.
Presently, for the treatment of depression and other what some claim are other types of mental disorders that are may or may not exist, selective serotonin reuptake inhibitors (SSRIs) are the drugs of choice by most prescribers today for a variety of mood disorders, including and primarily for the treatment of depressive disorders. The most severe of the depressive disorders is when one has a major depressive disorder, also called clinical depression or major depression. Symptoms of this type of depression, which is the most concerning due to its severity, include decreased or flat affect, decreased interest in activities once enjoyable, worthiness, guilt, regret, helplessness, and hopeless, to name a few of the diagnostic features that may be present with one who has such a major depressive disorder.
These SSRIs are known by some as third generation anti-depressants. Such drugs, drugs that affect the mind, are called psychotropic medications. SSRIs also include a few drugs in this class that include the addition of a norepinephrine uptake inhibitor added to the SSRI, and these drugs are referred to as SNRI medications, which combined with SSRIs, are the number 1 top therapeutic class of prescriptions presently, it has been reported. While there are several available SSRIs presently, it is believed that only two SNRIs are available, which are Cymbalta and Effexor. Some consider these classes of meds the next generation mood enhancers- after the benzodiazepine hype decades ago. Furthermore, regarding SNRIs, adding the additional agent of norepinepherine is presumed to increase the effectiveness of SSRIs by some.
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 known as the DSM, states that the definite etiology of depression remains a mystery and remains unknown with complete certainty. So a chemical imbalance in the brain is not proven to be the cause of mood disorders, it is only suspected as a result of limited scientific evidence. In fact, diagnosing mental diseases such as depression is based on subjective assessment only, as interpreted by the prescriber, so one could question the accuracy of such diagnoses.
Norepinepherine 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, as suggested earlier.
And depression may be combined with related mood disorders that may exist with certain patients. Anxiety usually exists with one who has a major depressive disorder. A objective diagnosis of these mental conditions lack complete accuracy, as they can only be defined conceptually, so the diagnosis or impression concluded by the patient’s doctor is dependent on subjective criteria, such as questionnaires and patient observation by the health care provider. Such questions come from what is known as a DSM book created by psychiatrists. Screening programs that have been used for identifying depressed patients have proven to be largely ineffective. A social patient history is uncertain and tricky as well, some have said. There is no objective diagnostic testing for depression to validate as to whether or not the disease is present. A health care provider has to assess as to whether certain diagnostic features are present to offer the diagnosis of major depression. This is further complicated by the fact that the exact cause of major depression is unknown.
Yet the diagnosis of depression in patients has increased quite a bit over the past few decades. Some have asked themselves and others- actually how many people are really and actually depressed? What is believed is that if one is determined to be cognitively impaired from a mental paradigm, then it may be major depression. If this is determined by a health care provider, than pharmacological therapy is considered reasonable and necessary, as well as psychotherapy either used with or in place of medicinal therapy.
It has been reported that around 10 percent of the U.S. population will at some point be affected by a major depressive disorder. Due to such factors as the likeliness of others being depressed often being discussed recently in the media and medical literature, that may not be completely accurate or thorough, depression and the treatment and diagnosis of this disorder has increased remarkably in a short period of time in the United States. This depression issue is further encouraged by those pharmaceutical companies that market medications for major depressive disorders. So more people seek treatment now for what they believe is a major depressive disorder they are experiencing, when in fact it may be intense sadness, perhaps, due to a loss of some sort in their lives. There is a difference, and health care providers should have the appropriate tools and knowledge to discriminate between the two states of mental conditions. Sadness is not a medical problem. Symptoms associated with an unfavorable mental state need to be excessive and chronic to be considered to have in fact the medical problem of a major depressive disorder, as stated by others.
In Time magazine’s June 16th 2008 cover story, it was reported that the military personnel in the Iraq war are pounding down SSRIs often. Every time there is a new war, there is a new drug, it seems. Yet the story may illustrate the frequent usage of these types of medications in a variety of different areas for different reasons. Some reasons may be valid and appropriate, yet others perhaps may not be reasonable for such medicinal therapy.
In regards to those pharmaceutical companies who make and market such psychotropic drugs in the manner that they do that largely is unknown to others, 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 that they currently promote to these doctors, as this aspect of the pharmaceutical industry clearly desires market growth of these psychoactive medications. Front groups to expand the market for these types of drugs have been known to occur as well, which have on occasion been developed if not supported by such companies.
Regardless, SSRIs and SRNIs are the preferred treatment methods if depression or other mood disorders that may be suspected by a health care provider- regardless of their specialty. Yet these drugs discussed clearly are not the only treatments, medicinally or otherwise, for depression and other related and suspected mental disease states or disorders. Patients should be aware of this fact as well as caregivers.
Over 30 million scripts of these types of meds that enhance serotonin saturation in the brain are written annually, and the franchise is around 20 billion dollars a year now, along with some of the meds costing over 3 dollars per tablet, it has been reported. 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 be launched as a 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 upon request of their makers to the FDA additional indications besides depression for some really questionable conditions, such as social phobia and premenstrual syndrome. Also included with indications that now exist with these types of medications include both generalized and social anxiety disorders, Obsessive Compulsive Disorder, Panic Disorder, Agoraphobia, Post Traumatic Stress Disorder, Bulimia, and stress disorders in general. I understand they are seeking indications for pain management as well with these SSRI or SRNI pharmaceuticals. This may need further review before the use of these drugs are expanded into other conditions that have not been considered or thoroughly studied in the past, I believe.
With some of these indications for these classes of drugs, I question as to whether or not they are actual and treatable disease states or non-medical problems. Yet with additional indications for particular drugs in these classes o medications, one can be assured that the market for these drugs will continue to grow, as more are prescribed these particular classes of drugs, even though some have suggested that these types of drugs are effective in only about half who take them. And some of the indications granted to drugs in these classes of medications may be considered disease mongering to grow the market share for particular drugs of this type. This is combined with drug companies who make these types of meds either forming or creating front groups in order to have more diagnosed with various medical problems that may not exist so their medication can be utilized to a greater extent through such methods as screening others, or exaggerating the prevalence of a particular medical condition that their medication may be indicated for and authorized by the FDA. Needless to say, such activities by pharmaceutical companies are deceptive, inappropriate, unreasonable, unnecessary, and clearly dangerous to others.
Perhaps of greater concern and danger with these particular psychotropics primarily involves the adverse effects associated with these types of drugs, which include suicidal thoughts and actions, violence, including acts of homicide, and aggression, to name a few, yet devastating, events that have occurred while one is taking a SSRI or SRNI. It has been reported that the makers of such drugs are suspected to have known about these toxic and dangerous effects of their drugs 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 for understandable reasons, which have included 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 of children, 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, combined with the true decreased efficacy of SSRIs in general, which is believed to be only 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 of such important information- Elliot Spitzer specifically was the catalyst for this awareness, as I recall. Furthermore, that drug is in the spotlight once again years later. Some believe the drug maker knew about possible risk to the youth as early as 1991. Yet did not disclose such danger associated with their drug to the public or the FDA, and this was done with intent.
And there are very serious questions about the use of SSRIs in children and adolescents regarding the possible damaging effects of these meds on them. For example, do the SSRIs correct or create brain states considered not within normal limits, which in effect would possibly cause harm rather than benefit a patient on such a drug? 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 self identity of such young people? Do adolescents in particular become dangerous or bizarre due to SSRIs interfering with the myelination occurring within 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 drugs, but not all who take these drugs. Yet health care providers possibly should be much more aware of these possibilities, possibly, along with the black box warning now on SSRI prescribing information for the youth that has existed since 1994.
Finally, if SSRIs or SNRIs are discontinued by a patient rapidly and without medical supervision, withdrawals are believed to be quite brutal that follow soon after the drug is not taken anymore by a former patient of these types of drugs, and may be a catalyst for suicide in itself, as not only are these drugs habit forming, but discontinuing these meds abruptly, I understand, leaves the brain in a state of neurochemical instability, as the neurons need to recalibrate after existing in a brain over-saturated with serotonin. This occurs to some degree with any psychotropic medication, yet the withdrawals can reach a state of danger for the victim in some classes of meds such as SSRIs and SNRIs, it is believed. And this seems to concern many.
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. Before these medications mentioned were developed, doctors praised trycyclics, another class of anti-depressants, in a similar manner some time ago. Considering the lack of efficacy that has been demonstrated objectively with these newer psychotropics, along with the deadly adverse events with these SSRI and SSNI meds only recently brought to the attention of others, other pharmacological and non- pharmalogical treatment options should probably be considered, but that is up to the discretion of the prescriber. And the perception of the benefits derived by these types of drugs may be flawed, as there has been no decrease in incidences of suicide or remission of depression since these drugs have been available, many have concluded. Furthermore, recent studies have suggested that the supplement, St. John’s Wart, has shown to be as effective as medicine for major depression.
It is my hope that such a prescriber rules out possible other etiologies for their patients’ mental conditions before they conclude that such a patient is suffering from true mental illness requiring the medications mentioned earlier, such as asking their patients about life stressors and other medications these patients have taken or are presently taking. Because at times, a doctor can in fact do harm without intent.
“I use to care, but now I take a pill for that.” --- Author unknown
Dan Abshear
Author’s note:
Addendum to this article based on the following link:

There are greater than 60 symptoms associated with one who is or may be depressed, and there are different degrees of depression. The number of symptoms expressed by one who suffers from depression determines the severity of their depression.

The characteristics associated with depression are affective, cognitive, and somatic.

For example, affective symptoms are the core symptoms of a depressed mood, and the term that one has a flat affect is an indication that one may be suffering from depression. These symptoms may include sadness, dissatisfaction, crying episodes, irritability, as well as social withdrawal. It should be noted that many events could cause the expression of such symptoms besides depression in itself.

Cognitive symptoms associated with depression may include pessimism, a sense of failure as well as guilt, suicidal ideation, and dislike of self.

Somatic symptoms may include insomnia, fatigue, weight change, and loss of interests, such as sex or other activities engaged in historically with a depressed patient. It should be noted that stress can cause such symptoms as well, in my opinion,

Dan Abshear