Sunday, August 17, 2008

The Antidepressant Warning Affair: What Really Happened?

This tale unfolds in three chapters:

Chapter One. Critics of the pharmaceutical industry amass evidence that trials showing an excess risk of suicidal behavior among children and adolescents taking many serotonin-type (SSRI) antidepressants had been suppressed for many years. Responding, regulatory agencies in the US and Europe issue label warnings on SSRI drugs (except for fluoxetine or Prozac) for pediatric use.

Chapter Two. The prescriptions of SSRI's for children decline. Studies are then published by child psychiatrists claiming to show that the immediate result has been a worrying upsurge in suicides among young people. The authors claim that what has happened is typical of regulatory excess, and that while a few cases of suicidal behavior may have been caused by these drugs, their widespread use in kids clearly prevented a far greater number of suicides from occurring--prevention that has now ceased as physicians are scared off by label warnings from using these drugs even where they could save lives. The industry critics then note, first, that many of these rise-in-suicide studies are poorly designed (for instance, assuming a decline in prescriptions but actually having no data to prove that); and second, that many of the authors of these Chapter Two studies have financial ties to the industry.

Lineberry TW, Bostwick JM, Beebe TJ, Decker PA. Impact of the FDA black box warning on physician antidepressant prescribing and practice patterns: opening Pandora's suicide box. Mayo Clin Proc 82:518-20, 2007.

Gibbons RD, Brown CH, Hur K, Marcus SM, et al. Early evidence on the effects of regulators' suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry 164:1356-63, 2007.

Chapter Three. More extensive and better designed studies appear from non-industry-funded sources. Olfson and Shaffer, for instance, note that the data Gibbons et al. relied on was a brief uptick in suicide rates at a single point in time, and that the best available data subsequently showed that this uptick had been a random event and not a sustained trend. In a more detailed study, Wheeler et al. looked at the UK situation, where the dropoff in SSRI pediatric prescriptions following the 2003 warning was much deeper than in the US, presumably creating a situation in which even more suicides would subsequently have occurred. On tracking long-term trends in both suicides and self-harm behavior, they found no effect of the abrupt change in prescribing of SSRIs on either.

Olfson M, Shaffer D. SSRI prescriptions and the rate of suicide. Am J Psychiatry 164:1907-8, 2007.

Wheeler BW, Gunnell D, Metcalfe C, Stephens P, Martin RM. The population impact on incidence of suicide and non-fatal self harm of regulatory action against the use of selective serotonin reuptake inhibitors in under 18s in the United Kingdom: ecological study. BMJ 336:542-5, 2008.

Comment: Anyone who had been following the literature on SSRIs generally knows that one of the major debates about pharmacologic treatment of depression in recent years is whether SSRI antidepressants as a group--quite apart from their risks--are demonstrably better than placebo in their average effectiveness. Given the difficulty in large-scale meta-analyses of demonstrating the effectiveness of this class of drugs, the claim that their widepread use was preventing many suicides, and the dropoff in their use led to a singificant increase in the suicide rate, was implausible on its face. As a family physician who prescribed many of these drugs (probably, in hindsight, far too many) for many years, I can testify to individual cases where the drugs appeared to be extremely effective. But here we are talking about population effects, not individual effects. The results of the more recent studies, showing no significant change in suicide rates, certainly appear overall to be more plausible, all things considered. And that, in turn, seems to suggest that the warnings regarding the increased risk of suicidal behavior among children and adolescents taking these drugs were prudent and evidence-based, and not the hysterical over-reaction that some industry-friendly physicians have alleged.


Anonymous said...

I'm wondering what the Industry tie is for the first paper you mention: Lineberry TW, Bostwick JM, Beebe TJ, Decker PA. Impact of the FDA black box warning on physician antidepressant prescribing and practice patterns: opening Pandora's suicide box. Mayo Clin Proc 82:518-20, 2007.


szimonsays said...

Well put. I have followed this controversy for a number of years and read extensively on the subject. It is very much as put here. It is very difficult to attribute suicide to one factor such as a drug but the studies have shown a real increase in risk, and the reality may be that the anti-depressants may be that awful "tipping point" at which a young person takes their own life on impulse. The psychiatric brotherhood doesn't want to see it like that. It is as if one person dying from a wasp sting by anaphylactic shock could not have been killed by the sting because thousands of others did not die from a sting. That is the logic being used. The fact is that without careful monitoring and involvement of family, young people take their lives because the drugs do push to the tipping point of impulsive action. The psychiatric brotherhood should look at competency in practice and the rates of suicide caused by these drugs will likely decline.
Caring for troubled people takes a lot more than scribbling a prescription on a pad.

Anonymous said...

Presently, for the treatment of depression and other mental disorders, some of these disorders are questionable regarding thier existence, the preferred choice of medicinal treatment are a class of medications called selective serotonin reuptake inhibitors, referred to as SSRIs, as they 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 Effexor and Cymbalta. Presently, some compare the usage and popularity of these classes of meds as that of the usage of tranquilizers decades ago.

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 and diseases is only theoretical. In fact, the psychiatrist’s bible, which is called the DSM, states that the definite etiology of depression remains a mystery and is unknown. So a claim of a chemical imbalance in the brain as a reason for depression is not proven to be the cause of this and other mood disorders, it is only suspected based on limited science, which may or may not be valid. Observation by one's doctor is usually the determining factor for such a diagnosis.

Norepinephrine is a stress hormone, which many believe help those who have such mood disorders as depression. Perhaps this is now added to SSRIs for additional efficacy for those treated with these medications.

And depression is only one of those mood disorders, yet possibly the most devastating one. Once again, 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, as there is no diagnostic testing available to conclude objective diagnosis of such disorders. However, the diagnosis of depression in patients has increased quite a bit over the decades. While most likely a real disease, most will agree, misdiagnosis does occur due to the subjective assessment that determines the disease, as perhaps one out of every four people diagnosed with depression is inaccurate.

Several decades ago, less than 1 percent of the U.S. population were thought to have depression. Today, it is believed that about 10 percent of the population have depression at some time in their lives. Why this great increase in the growth in the assessment 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 various forms of support, as this industry clearly desires market growth of their psychotropic products, such as SSRIs, since clearly this is part of their nature and objective as a pharmaceutical company. Regardless, SSRIs and SRNIs are the preferred treatment methods if depression or other certain mood disorders that may be suspected by a doctor.

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 this month and is expected to be promoted primarily for the treatment for menopause. Conversely, 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’. As years passed, this drug was preferred for children with depression. Also, a book was written praising Prozac as a euphoric entity for all to experience.

Furthermore, these meds have received additional indications for 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. With social phobia, many would say that is a personality trait and, in my opinion, is synonomous with shyness, which probably should not be labeled a treatable disease as well. There are other indications for certain behavioral manifestations with the different SSRIs or SRNIs. So the market continues to grow with these meds- assisted by thier manufacturers. Yet, it is believed that these meds are effective in only about half of those who take them. Also, the makers of such meds create such conditions for utilization of these types of medications, in my opinion, and are active with related support groups who are funded by the makers of such drugs, such as sponsoring screenings for the indicated and not indicated conditions of their meds, including children and adolescents in particular, it is believed. Yet depression, which has clearly has been proven to be devastating to the victim, such screenings are controversial due to possible bias involved in seeking those with mental illness in this manner.

More concerning, however, is the adverse effects associated with SSRIs and SRNIs, which include suicidal thoughts and actions, as well as violence, including acts of homicide and aggression. The associations with these actions have been established with these types of meds. While most are approved for use in adults only, prescribing these meds to children and adolescents has drawn the most attention to others through the media. The reasons for this attention are the off-label use of these meds in this population, and the association with suicide. 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 and true efficacy of certain types of SSRI meds, including the decreased efficacy of SSRIs, which is believed to be only less than 10 percent more effective than a placebo, until ultimately the makers of such drugs were forced to do so. Paxil, for example, caught the attention of the government regarding these issues some time ago for hiding and not presenting such important information to others, for example.

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 may worsen thier mental state? Are adolescents depressed, or just experiencing what was once considered normal teenage angst? Do SSRIs have an effect on the brain development and their identity? 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 exists in some who take such meds, but not all who take these meds. Yet more need to be aware of such possibilities, some say.

Finally, if SSRIs are discontinued by those who have taken them for certain periods of time, withdrawals have been reported 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 leaves the brain in a state of neurochemical instability, as the neurons are recalibrating upon discontinuation of the SSRI after being altered by the med to some degree. This occurs to some level with any psychotropic med, yet the withdrawals can reach a state of danger for the victim in some classes of meds such as the case with SSRIs.

SSRIs and SRNIs have been claimed by doctors and patients to be extremely beneficial for the patient’s well -being regarding the patient’s issues involved with thier mental illness suspected, such as depression, yet the risk factors associated with this class of medications may outweigh any perceived benefit for the patient taking such a drug, and this may want to be explored more by others. 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 at the discretion of your prescriber.

“I use to care, but now I take a pill for that.” --- Author unknown

Dan Abshear