Some of you have probably read that taking an aspirin every day can decrease your chances of having a heart attack. But will doing this really improve your quality of life? Or prolong your life? If so, how much? These sorts of questions are not necessarily unique to this particular treatment… rather, they reflect general concerns about the extent to which treatments have a meaningful impact on peoples’ lives. And these same concerns lie at the heart of recent debates about the effectiveness of antidepressants.
The FDA’s approval of Prozac as a treatment for depression in the 1987 had a dramatic impact on the field of psychiatry, and arguably on Western medicine as a whole. Since then, newer classes of antidepressant medications have been developed that seem to be just as effective as Prozac, but have even fewer side effects. Plus, these medications are now prescribed for a wide range of problems other than depression, ranging from anxiety to sleep and pain problems. So it’s not too surprising that millions of people are taking antidepressants. But do they really help combat depression? Is the name of this class of drugs misleading?
Two recent articles have incited some debate over this very issue. In both cases, the authors systematically reviewed years and years of studies examining the effectiveness of antidepressants, and both reached strikingly similar conclusions – for people with mild or moderate levels of depression, the advantage of antidepressants over a simple sugar pill is NOT really large enough to make a meaningful difference in the lives of patients. And even though the advantage was more impressive for severely depressed patients, this seemed to reflect the sugar pills having less effect this group, rather than an increase in the benefits of antidepressants. Not surprisingly, both articles got some attention in the popular media when they were published. As is often the case, the findings were summarized in an overly simplified fashion – in essence, antidepressants don’t really work (here is one example). But is this sending the right message to the general public? And if so, should people stop taking antidepressants?
The controversy surrounding these recent review articles hinges on an issue that researchers have termed “clinical significance”. Traditionally, the standard for evaluating a new treatment in clinical trials is purely statistical – was the treatment group doing better than the comparison group by the end of trial, and can we be confident that the results weren’t just based on chance? But some critics argue that this doesn’t set the bar very high – after all, if you are conducting a very large study (or if there have been lots of studies), a very small improvement could be “statistically significant.” Meanwhile, the advantages for people’s actual lives might be trivial. For example, taking an aspirin each day might decreases your chances of having a heart attack by about 33%, but it only decreased your chances of dying from a heart attack by about 5% (and some more recent reviews suggest they may be even smaller than this). In light of this, some have argued that a daily aspirin regiment isn’t really worth the hype, especially for those who are in good health. Based on these sorts of debates, there is a growing interest in trying to show that the benefits of treatments are clinically significant – in other words, that treatments actually make a difference in people’s lives.
Unfortunately, demonstrating clinical significance can be a bit tricky. As a result, there are lots of different ways to do it – such as comparing patients’ symptoms at the end of treatment to those who never suffered from the problem to begin with, asking their overall satisfaction with their lives, or trying to determine if there was important changes in their day-to-day lives (like being able to return to work). In both reviews, the authors examined clinical significance purely in terms of how much peoples’ symptoms decreased. While this is a perfectly legitimate way to look at clinical significance, it does have some limitations. So, even though these new findings do cast some doubt on whether antidepressants yield clinically significant benefits (especially for those who aren’t severely depressed), it isn’t clear whether other methods of gauging clinical significance would have led to a different conclusion.
At the same time, it is important to keep in mind that people’s decisions about whether or not to choose a particular treatment aren’t just based upon the significance of the benefits alone. Rather, the potential benefits should be weighed against the costs. Going back to the aspirin example, even if the benefits are quite small, you might still decide that it is worthwhile to start a daily aspirin regiment since it is simple and fairly cheap. With antidepressants, the formal costs will vary quite a bit from one person to the next, based in part on things like health insurance. However, antidepressants also have a host of possible side effects, including things like weight gain and decreased sex drive, which should be taken into consideration when weighing the costs and benefits. In the same vein, physicians generally discourage daily aspirin consumption for patients with medical conditions that place them at risk for serious side effects (like hypertension).
In addition to weighing the benefits of a treatment against the costs, treatment decisions can and should be influenced by the alternatives that are available. For depression, the primary alternative is psychotherapy. While several different kinds of therapy can be helpful for depression, there are still some similar concerns about their clinical significance. And while there have been a number of attempts to determine whether therapy or medication works better for depression, there doesn’t seem to be a clear “winner.” But the real irony of these efforts is that people don’t necessarily have to choose… just like I can decide to exercise and take an aspirin everyday to reduce my risk of heart attack, medication and therapy can be combined to treat depression. And importantly, there is some evidence to suggest that the combination works better than either alone.
Here’s the bottom line… while the results from these two important review articles raise some legitimate concerns about the real-world benefits of taking antidepressants, the issue is by no means settled. At the same time, people’s decisions about whether or not to take antidepressants (or any medication for that matter) can and should be influenced by other factors, like the costs associated with taking them and available alternatives. Meanwhile, be careful when you read about new research findings in the popular media – they often gloss over some details which may seem trivial, but are actually quite important.
Sources Cited:
Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, & Johnson BT (2008). Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS medicine, 5 (2) PMID: 18303940
Fournier, J., DeRubeis, R., Hollon, S., Dimidjian, S., Amsterdam, J., Shelton, R., & Fawcett, J. (2010). Antidepressant Drug Effects and Depression Severity: A Patient-Level Meta-analysis JAMA: The Journal of the American Medical Association, 303 (1), 47-53 DOI: 10.1001/jama.2009.1943
Yusuf, S., Wittes, J., & Friedman, L. (1988). Overview of results of randomized clinical trials in heart disease. II. Unstable angina, heart failure, primary prevention with aspirin, and risk factor modification JAMA: The Journal of the American Medical Association, 260 (15), 2259-2263 DOI: 10.1001/jama.260.15.2259
Radical idea: Why don’t we ask people for whom anti-depressants have been successful to describe how taking the drugs has apparently improved their lives- which will be clinically significant to them and their therapists? I’ve been looking into the pharmacogenetics of some drugs and it seems that as well as individual variation of multiple and unknown origins, the genetically determined ability of the body to deal with a dose of anti-depressant could well be a major factor in response. Traditional clinical trials use single dose (or sometimes a small range of doses) of anti-depressant, giving the people who only need a small dose dreadful side effects and hardly influencing the mood of those who need a really high dose. The result is maybe 40 to 50% of trial participants report some positive change, but no clear benefit shows up because the sample is too heterogeneous at baseline. I know you get interesting results with attention and executive functioning, and that’s a large part of how antidepressants exert their end effects, but ordinary humans don’t describe their feelings and behaviours that way. Why don’t we do some PGX tests, stratify subjects on the results (and the usual co-variates) and do some really good qualitative research alongside the crunchy numbers? After all, we’re not trying to kill off a certain percentage of cancer cells, or increase blood potassium- we’re dealing with the warm, fuzzy chaos of human emotion. I’d love to get together with someone suitable and do this as a PhD project, but there is no one around even vaguely suitable in my home department of public health! PS. I share brainspace with an individual who only responds to 600mg of a well known antidepressant, where the level prescribed in general practice is only 75 to 150mg. I know this leaves a large number of depressed people ill, but there is no hope of getting them referred to a specialist for a higher dose because they’re not responding even slightly to the low dose! Without some more complex research we are doing some anti-depressants an injustice and depriving the community of many viable members.
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