Tuesday, February 26, 2008

Antidepressants: Meet the New News, Same as the Old News

A recent meta-analysis from Irving Kirsch and colleagues (available here in PLoS Medicine) indicated that for the great majority of depressed people, the advantage of antidepressants over placebo was small. No kidding. For the most part, this study actually says nothing new. In fact, the same authors did a very similar study not once, but twice, showing that antidepressants were mostly hype (1, 2). So we've known for years that there is a good deal of publication bias (i.e., burying negative results) and that the difference between antidepressants and placebos is quite modest. Wait, you didn't know that? Ah, therein lies the problem. News such as this survives for one to two media cycles then vanishes, as the media attends to more important matters, such as Britney's latest bout of trouble, who won an Oscar, and the like. I mean no disrespect to Kirsch and his colleagues -- their work is tremendously important -- but shouldn't the media make damn sure that the public is aware that the collection of published and unpublished data from clinical trials indicates that antidepressants give only a small benefit over placebo? Or should we learn more about K-Fed, Michael Jackson, and various other trivia?

Note that there is, indeed, a small benefit for drug over placebo. Is the small benefit worth the side effects? Well, that's a different question... An even better question is "Please define the term 'small benefit'..." The benefits for medication over placebo appear to be an underwhelming 1.8 points on the Hamilton Depression Rating Scale. Considering that it is a 52-point scale, with many of those points being determined by ratings of sleep and anxiety, any advantage for a drug relative to a placebo might be unrelated to the core symptoms of depression.

What this study adds is that the most severely depressed patients appear to show somewhat more benefit on antidepressants relative to placebo. Their analyses indicate that the placebo response tends to decline among the most severe cases of depression while the antidepressant effect remains about the same. But most people who take antidepressants are not severely depressed. And, shock of all shocks, Kirsch and colleagues found that data from some trials showing no advantage for drug over placebo were simply not available.

Warning: This paragraph is a bit wonky, so you might want to skip ahead. The authors adopted a standard that anything under an effect size of .50 is not clinically significant, which is a standard adopted by the National Institute of Clinical Excellence (NICE) in the UK. According to conventional criteria (e.g., Cohen), an effect size of .50 translates to a moderate effect and an effect size of .20 translates into a small effect. The average effect in this analysis for drug over placebo was .32. Such an effect is certainly not impressive, but should not be confused with no effect. The problem (as noted above) is we don't really know what a small effect means -- on what items on the rating scale was there typically a difference between drug and placebo? Were these items relevant to depression? In any individual study, one can cherry pick items from a rating scale and show a difference favoring a drug, but I'd be more interested in what a large meta-analysis such as Kirsch's most recent study would show on the individual items of the HAM-D or other rating scales. One more thing: The effect for antidepressants really looks bad at the lowest end of severity. Go to Table 1 in the study and look at the effect sizes for the studies where the baseline depression rating is under 24. My own back of the envelope calculations, factoring in sample size, gives an effect size of about .10, which equates to about nothing for the least depressed folks.

Fortunately, the Independent has a nice little story on the topic, though the headline is a little obnoxious. I quote as follows:

Alternative treatments for depression, such as counselling or physical exercise, should be tried first, Professor Kirsch said. The pharmaceutical companies had withheld data that was available to the licensing authorities so that doctors and patients did not understand the true efficacy, or lack of it, of the drugs.

"This has been the frustration. It has made it very difficult to answer the question of whether the drugs work. The pharmaceutical companies should be obliged when they get a drug licensed to make all the data available to the public. When you analyse all the trials of these SSRIs, both published and unpublished, it leads you to more sober conclusions," he said.

Tim Kendall, deputy director of the Royal College of Psychiatrists' research unit, said the findings, if proved true, would not be surprising. As head of the National Collaborating Centre for Nice guidelines on mental health, he said it had proved impossible to get access to unpublished trials in the past.

"The companies have this data but they will not release it. When we were drawing up the guidelines on prescribing antidepressants to children [in 2004] we wrote to all the companies asking for it but they said no. The Government pledged in its manifesto to compel the drug companies to give access to their data but that commitment has not been met."

But, to be fair and balanced, here are the critiques of the pharma companies, which provide the usual nonspecific and bogus mumbo-jumbo

GlaxoSmithKline, makers of Seroxat, said the authors of the study had "failed to acknowledge" the very positive benefits of SSRIs and their conclusions were "at odds with the very positive benefits seen in actual clinical practice." A spokesperson added: "This one study should not be used to cause unnecessary alarm for patients."

Lilly said in a statement: "Extensive scientific and medical experience has demonstrated that fluoxetine [Prozac] is an effective antidepressant.

Wyeth said: "We recognise the need for both pharmacological and non-pharmacological treatments for depression."

If there is such "extensive" evidence about the "very positive" effects of these medications, why wouldn't a single one of these companies cite a single study? Oh, right, because Kirsch already examined the relevant studies. This study, in combination with the recent study in the New England Journal of Medicine that showed how every single drug company with an antidepressant on the market twisted their data regarding the efficacy of antidepressants, should serve as a wakeup call for those who have not been paying attention to the issues of mediocre antidepressant efficacy and how inconvenient data are buried. Overplay the positive data, hide or lie about the negative data. As for depressed patients: Let Them Eat Prozac.

Also see discussion at Furious Seasons.


Anonymous said...

As the director of Novus Medical Detox, I often see patients who are on alcohol or opioids, central nervous system depressants, also taking antidepressants. When they detox they find they don't need the antidepressants.

This is good news because a Swedish study showed that 52% of the 2006 suicides by women on antidepressants. Since antidepressants work no better than placebos and are less effective than exercise in dealing with depression.

There is a prescription drug epidemic and these are leaders in the list of terribe abuses.

Steve Hayes

Anonymous said...

Do Serotonin drugs' Risks Outweigh Any Benefits?

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