How Blind is Double-Blind?

There's a rather timely article in the current American Journal of Psychiatry: Assuring That Double-Blind Is Blind.

Generally, when the list of the authors' conflicts of interest (550 words) is nearly as long as the text of the paper (740 words), it's not a good sign, but this one isn't bad. Perlis et al remind us that if you do a double-blind placebo controlled trial:

The blind may be compromised in a variety of ways, however, beginning with differences in medication taste or smell. Of particular concern may be the emergence of adverse effects, particularly when those adverse effects are known to be associated with a specific medication ... Indeed, when the degree of unblinding is assessed in antidepressant trials, multiple reports suggest that it is extensive: at least three-quarters of patients are typically able to correctly guess at their treatment assignment.

The point of a placebo-controlled trial is that neither the patients nor their doctors know whether they're getting the placebo or the real drug. Hence the strength of the placebo effect should be the same in each group, allowing the "real" drug effect to be measured.

But if the drug causes side effects, as pretty much all do, then people could work out which group they're in by noticing whether they're feeling side effects or not. This might enhance the placebo effect in the drug group, and make the drug seem to work better than it really does. Or it might not. But the possibility that it might is worrying.

This is called the active placebo effect. It's why I'm skeptical of claims that scopolamine and ketamine have rapid-acting but short lived antidepressant effects. I may be wrong, but while both of these drugs have been shown to work better than placebo, both have very pronounced subjective effects, so there's no chance the blind will have been intact.

Whether the active placebo effect also underlies the efficacy of established antidepressants like Prozac is very controversial. There have been 9 trials comparing antidepressants to active placebos, i.e. drugs that have similar side effects to antidepressants and that should therefore help to preserve the blind. (The active placebos were all atropine which is basically the same as scopolamine.)

The trials were reviewed by antidepressant critic Joanna Moncrieff et al who found that the overall effect size of antidepressants vs. active placebos was d = 0.39. That's not very high, although it's not too bad, and ironically it's actually higher than the effect that Moncrieff's friend and fellow Prozac-baiter Irving Kirsch found in his famous 2008 antidepressant vs. sugar pill placebo meta-analysis, d=0.32. So if you take that seriously, the active placebo effect plays no part in antidepressant efficacy. However the active placebo trials are mostly small and old, so to be honest, we don't really know.

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A point that's often overlooked is that a drug could have an active placebo effect via having a "real" psychoactive treatment effect. Diazepam (Valium), for example, has basically no peripheral side effects at all: unlike scopolamine it doesn't cause dry mouth, nausea, etc. But it is a tranquillizer; it causes calmness and, at higher doses, sleep. They're pretty noticeable. So if you were to give a depressed person Valium and tell them that it's not only a tranquillizer, it's an antidepressant, then the active placebo problem would arise.

In fact, any active drug will also produce active placebo effects - almost by definition, if you think about it. These may be hard to disentangle from the "real" effects. Say you're anxious about giving a speech so you take some diazepam hoping to feel calmer. A short while later you feel the lovely warm tranquillizing feeling setting in. Phew, you're calm now, anxiety's gone, the speech will be no worry. That thought might well be tranquillizing in itself. In other words the anti-anxiety effects of diazepam are partially driven by active placebo responses due to... the anti-anxiety effects of diazepam.

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This leads onto another point. Suppose a drug has a genuine effect which improves some of the symptoms of a disease. Does that drug "treat" that disease? In a weak sense, yes, and it might be a helpful drug, but it's not a specific treatment. Morphine's very helpful in cancer, because it treats pain, but it doesn't cure cancer. Likewise insomnia is a symptom of depression, but we feel that in order to qualify as an antidepressant a drug has to treat the core symptoms: mood, anxiety, etc. rather than just being a sleeping pill.

But suppose someone suffered from low mood and you gave them a treatment which stopped them feeling any moods or emotions. That solves their low mood problem: no mood, no problem. But is that a specific treatment for depression? It's a bit of a grey area, but many would say no.

Many people say that this is exactly what SSRI antidepressants do: they blunt your emotions. That doesn't mean they're not helpful in depression: a lot of people find them very useful. I did. But then are they really "antidepressants", or just anti-mood? SSRIs are the drugs of choice not just for depression but also most anxiety disorders, and obsessive-compulsive disorder, etc. In fact they work better in OCD than they do in depression, relative to placebo. So are SSRIs actually antiobsessives that happen to be helpful in some cases of depression? Good question.

Here's Chris Rock on the issue of non-specific effects...

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Perhaps an ideal clinical trial of a drug for a psychiatric condition should have 4 groups: the drug you're studying, another psychotropic with non-specific effects (e.g. Valium, or caffeine if you want a stimulant), an active placebo with purely peripheral side effects, and sugar pills. But even then, if the active drug performed better than the other 3 groups, a die-hard skeptic could say that maybe it's just more effectively causing non-specific sedation, or blunting, or whatever, than the Valium. Ultimately, a randomized controlled trial can never prove that a psychotropic drug has a specific as opposed to a non-specific effect.

So where do we stand? Does that mean we don't know what drugs do? No - unless we're some cloistered soul who only reads papers as opposed to talking to people, reading subjective reports, or taking drugs themselves. I know what alcohol does, not because I've read papers about it, but because I've drunk it. I've also been depressed and taken antidepressants, and for what it's worth, in my experience, some of the drugs currently marketed as antidepressants do have a specific anti-depression effect, although others don't. Overall, though, my view is that we know surprisingly little about what antidepressants actually do.

Perlis RH, Ostacher M, Fava M, Nierenberg AA, Sachs GS, & Rosenbaum JF (2010). Assuring that double-blind is blind. The American journal of psychiatry, 167 (3), 250-2 PMID: 20194487

Moncrieff J, Wessely S, & Hardy R (2004). Active placebos versus antidepressants for depression. Cochrane database of systematic reviews (Online) (1) PMID: 14974002