As you'll recall, the point of a double-blind placebo-controlled trial is that
neither the treating clinician nor the patient knows which condition the
patient is in.
Why is this
important?
Patients’ belief that they are being treated with a
medication can cause them to expect to get better. As a result, they may notice signs of improvement, even if
the drug doesn’t really do anything. So if we give one group the “brand new drug” and the other group
nothing, then the treated group will almost always do better.
Instead, we give both groups something that looks like a
treatment. In fact, it must look
identical (because some research suggests that certain pill colours and sizes are seen as
more potent than others). If there
is an expectancy effect, then it should appear equally in the groups getting
the placebo and the active medication. Any differences in the effect between the groups would have to be due to
the active ingredient in the pill.
Remind me why the clinician has to be blind.
We all communicate nonverbally. A physician who hands us a prescription confidently will
produce more of an expectancy effect (“This’ll clear up your problem!”) than
one who exhibits shame, anxiety, or an apologetic manner (“Sorry I don’t have
anything more effective to offer you”). If the clinician knows which medication a patient is receiving, he or
she might behave differently with clients receiving the real thing than with those
receiving the fake. So it’s vital
the clinician not know.
Similarly, it’s important that whoever is doing the
evaluation of the patient (whether that is the treating clinician or someone
else) not know which group the patient is in. If the evaluator really hopes that the test drug works,
people who got the drug may be scored as more improved than those who got the
placebo – even if the evaluator is trying hard to be even-handed.
So with all these precautions, patients must not know what
drug they’re getting, right?
You’d think so. But no. The problem is that
there are no perfect medications that change the target symptom (depression,
psoriasis, heart rate) and nothing else. Virtually every medication has side effects.
If you are in a drug trial and you notice that your hair is
dry, you have a metallic taste in your mouth, and your libido is gone, you
might very easily guess that the pill you are taking isn’t just a jelly
bean. In fact, in antidepressant trials patients are sometimes
asked at the end of the study “So, any guesses whether you got the test drug or
the placebo?” Antidepressants are
notoriously “buggy” with side effects, so patients tend to get the right
answer. As a result, the
supposedly blind trial isn’t blind at all.
If patients are getting all kinds of side effects they will
strongly suspect they are on the active medication, and they may experience a
stronger expectancy effect as a result. “I must be getting the real thing so maybe I really will get better.”
There is a problem even if the drug has no side
effects. Imagine a stunningly
effective drug that eradicates the problem symptom completely. Patients in the medication condition
will notice the vast improvement in their condition and will realize that they
must be on the real thing, effectively unblinding the study. But this will be a result of the real
effectiveness of the drug. A
bigger problem is when the side effects give the story away – potentially making
an ineffective medication look better than it really is.
So what?
So even in a well-designed placebo control trial, the study
may not actually be blind. As a
result, patients may have a greater expectancy effect in the genuine-drug
condition than in the placebo condition. The study will show that the drug is more effective than placebo, when
in reality the drug condition only had a stronger placebo effect than the sugar
pill.
How big a problem is
this?
No one knows.
Is there any solution?
Yes. Use a
placebo that has side effects. Instead of a sugar pill, we can use an existing medication that is not
thought to have an effect on the condition that is being studied. So if we are looking at, say,
depression, we could compare our new antidepressant with a drug that produces
similar side effects but that has never been shown to be effective against
depression. These are called “active
placebos.”
Does anyone do this?
It's not done often. In 2004, the Cochrane Collaboration (an organization that conducts reasonably rigourous analyses of the general trend of medical data) published a review of studies in which antidepressants were compared to active placebos (Moncrieff, Wessely, & Hardy, 2004). They found nine such studies - not a particularly impressive number.
Only two of the nine demonstrated a consistent statistically significant difference between the antidepressant and the active placebo. When the studies were combined, the overall effect size (the difference between drug and active placebo) was 0.39 standard deviations - a relatively weak treatment effect. When one particularly positive trial was not included, the effect size dwindled to 0.17 standard deviations. These differences are smaller than the differences that are usually found when antidepressants are compared to inactive placebo.
The United Kingdom's National Institute for Health and Clinical Excellence recently chose an effect size of 0.50 as a lower cutoff to represent an effect large enough to be considered clinically (as opposed to statistically) significant. Not everyone agrees with the cutoff, which is somewhat arbitrary, but these findings for antidepressants fall below it.
Unlike some reviews that find more powerful drug-placebo differences in severely depressed populations, the studies of inpatient populations produced weaker effects than those of outpatient populations.
This review of a few studies should not be used to conclude that antidepressants are nothing more than active placebo. But it’s not exactly a ringing
endorsement, either. The authors concluded that standard drug trials using inactive placebos ("sugar pills") might overestimate drug effects because subjects often figure out which condition they are in and develop higher expectations when they have side effects than when they do not.
It would be nice to see more studies comparing antidepressant
medication with active placebo, to see if we can demonstrate a genuine drug effect that isn't based on patient expectations. Until
we do this, some of our former optimism about the antidepressant drug class must be tempered with a bit of skepticism.
Reference
Moncrieff, J, Wessely, S, & Hardy, R Active placebos versus antidepressants for depression. Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD003012.
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