The Frontal Cortex

Prozac and Placebos

Lots of attention has been paid to the latest review/meta-analysis demonstrating that popular antidepressant medications don’t seem to be that much more effective than placebos. While this certainly isn’t the first time someone has demonstrated that Prozac is only mildly more useful than a sugar pill (unless, that is, you fall into the “severely depressed” category), this review was noteworthy because it consisted mainly of previously unpublished studies done by the drug makers before the drugs were put on sale. As Time magazine notes, this allows the researchers to “avoid a bias that often plagues reviews of previous research: the tendency for conclusive positive results to be published, sometimes more than once, and thus over-represented, while mediocre results can be ignored or even swept under the rug.”

That said, the study does come with one big caveat: the trials it analyzed are all 6-8 weeks long. In that short time frame, Prozac is often no better than a placebo. (Keep in mind that SSRI’s rarely produce any positive benefits for the first several weeks, a phenomenon known as the Prozac lag.) However, the performance gap between placebos and SSRI’s tends to widen the longer a person is taking the drug. After a while, the placebo effect tends to wear off, which is why people on an “active drug” are less likely to relapse.

And then there’s the meta problem of meta-analyses like this. If a large percentage of the SSRI benefit comes from the placebo effect – people expect the drug to work, and so it works – then learning that Prozac isn’t actually that effective might actually make it less effective. It’s long been recognized that both placebo response and drug response for antidepressants have steadily increased over time. Much of this increase is most likely due to marketing. People have been trained by Eli Lilly’s ads to believe that a little blue pill will make them less depressed, and so they end up significantly less depressed. A little self-delusion might not be such a bad thing after all.*

*Obviously, it’s important to know that our drugs aren’t that much more effective than a sugar pill. Studies like this are extremely important. But it’s also worth remembering that the placebo effect also produces real changes in the brain, which have real therapeutic benefits.


  1. #1 Mike
    February 27, 2008

    Peter Kramer wrote a piece about this. Basically you can’t lump all the trials together, because some aren’t constructed well enough to distinguish the drug from the placebo.
    “In the rush to bring patented compounds to market, pharmaceutical houses sometimes enroll research subjects who barely meet criteria for the condition under study (in this case, depression). In some early trials, researchers may purposely use low doses; the idea is to squeak by the FDA’s minimum efficacy requirements without raising concerns about side effects. Because the subjects do not have the relevant disease, and because normal people’s moods wax and wane, these sloppy studies have high placebo response rates.

    “And then the research tends not to get published, because it’s simply not credible. Or the consequence is worse yet. Every researcher in the field can name a promising substance that was lost for patient use as a result of poor study design or overeager recruitment of subjects, resulting in astronomical placebo response rates.”

  2. #2 MattXIV
    February 27, 2008

    My understanding is that the effects were statistically significant overall, but less than the cutoff they’re comparing them to as a standard for clinical usefulness (1.8 vs 3 points on HRSD) used for forming recommendations in the UK. Mean differences don’t distinguish between a drug that has a small impact on a large segment of the patient population and a drug that has large impact on a small segment of the patient population. Given the worries about overly broad diagnostic criteria for depression, the fact that it’s well known that response to SSRIs and SNRIs does vary quite a bit from patient to patient, and that the researchers did find a subgroup where the magnitude of the difference was more clinically significant the later is quite plausible.

    This leads to one of my qualms about how EBM gets implemented sometimes. There’s a tendency to treat a population rather than a patient, going directly to the drug that produces the best average improvement for the demographic the patient belongs to. Sometimes, this can be problematic since a drug that creates a substantial improvement for 10% of the patients will get passed over for a drug that creates a small improvement for 60% of the patients, since the tendency is to settle on the first thing that works. The clinical trial format, where the question is whether the particular drug can reliably beat a placebo, is different from the trial and error approach of clinical practice where you keep trying different things until you find one that works.

  3. #3 Rachael
    February 28, 2008

    Everybody has very interesting comments.

    The only thing I would say is that this is not new news, and maybe not such a bad thing after all. I think the real problem is when these drugs are prescribed external to psychotherapy… as is the case with a close relative of mine, who, for more than 10 years, has been seeing a therapist who writes large prescriptions for anything she asks. This goes on until she hears about another new/exciting drug or she has another suicide attempt. Not surprisingly, her condition has not improved during this time.

    The idea that the little blue pill “makes you happy” is an underlying bias of public opinion that contributes to the stigma surrounding treatment of psychiatric disorders. Personally, I feel this attitude is dangerous to those being treated. The little blue pill isn’t a stimulant, and most pyschiatric medications do not elevate mood. The medication doesn’t make a person happy absent other factors; it enables the person to elevate their own mood. “Enabling” versus “doing” is a big distinction to be aware of. If the person lacks the life skill required to elevate their own mood, the medication won’t “work”. If something non-pharmaceutical (ie, a belief, or hope) can enable the person to jump out of their cognitive dysfunction, you’ve got a “placebo” effect.

    None of these pills are a cure for psychiatric disorders… does anybody believe our mental function is that simple anyway? These medications are tools for psychiatrists to help their patients escape a dysfunctional state, and it is impossible to say whether the tool works external to its required counterpart of high quality psychotherapy.

  4. #4 Sky High
    February 29, 2008

    If “they” say that anti-depressants work through the placebo effect then “they” can also say that all these school shootings are only placebo effect as well.

    And at this point, “they” are probably Lawyers more than Doctors or Scientists. Sorry to be rude, but this is bothering me a whole lot lately.

  5. #5 REkzkaRZ
    March 5, 2008

    I donít appreciate your arguments mislabeling the power of belief as the power of delusion.

    Iím not a religious person, but humans are creatures of belief. We frame our realities in cages constructed of beliefs.

    Before atoms, there were other concepts of matter, and surely there will be concepts later disproving our current beliefs.

    The placebo-effect is not proof that delusion / deception are effective, it is the proof of the power of the human mind and belief.

    Radiolabís mis-direction on this area is deeply upsetting as well.