Ben Goldacre

The Guardian,

Saturday March 1 2008

It was fun to hear universal jubilation over the new meta-analysis showing once again that some antidepressants aren’t much cop in mild or moderate depression: most of all on the Today programme, where a newsreader said the industry was contesting the study on the basis that it was not in line “with patient experience”. I’ve always said that homeopaths mimic big pharma in their marketing spiel, but this is the first time I’ve seen it done the other way around, so bravo to pill peddlers of all shades.

In fact the new study added nothing (and it was ridiculously badly reported, see further down this page): we already knew that antidepressants perform only marginally better than placebo, and the National Institute for Health and Clinical Excellence guidelines have actively advised against using them in milder depression since 2004.

But the more interesting questions are around placebo.

Do drugs stop working if you know they are little better than a sugar pill? And do cultural factors, like our collective faith in a treatment, have a measurable effect on the benefits? On this, there has been a only tiny amount of highly tenuous research.

Firstly, a study by Daniel Moerman looked at 117 studies of ulcer drugs from 1975 to 1994 and found that the drugs may interact in a way you might not expect: culturally, rather than pharmacodynamically.

Cimetidine was one of the first anti-ulcer drugs on the market, and it is still in use today. In 1975, when it was brand new, it eradicated 80% of ulcers, on average, in various different trials. But as time passed the success rate of cimetidine – this very same drug – deteriorated to just 50%.

This deterioration seems to have occurred particularly after the introduction of ranitidine, a competing and supposedly superior drug.

There are various possible interpretations of this finding: it’s possible, of course, that it was a function of changing research protocols. But one possibility is that the older drug became less effective after new ones were brought in, because of deteriorating medical belief in it.

Another study from 2002 looked at 75 trials of antidepressants over the past 20 years, but looked only at the response in the placebo arms of the trials, and found that the response to placebo has increased significantly in recent years (as has the response to medication): perhaps our expectations of those drugs have increased, or perhaps, conversely to our earlier example, the trial designs have become systematically more flattering. I’m giving you tenuous data, on an interesting area, because I know you’re adult enough to cope with ambiguity.

But what if you just come right out and tell somebody, without any ambiguity, that they are taking a placebo? One classic study from 1965 offers a clue, although it was small and without a control group, so once again, buyer beware.

They gave a pink placebo pill three times a day to patients they termed “neurotic”, and the explanation given to the patients was startlingly clear about what was going on.

Here is the standardised script which was prepared, and carefully read out to each patient:

“Mr Doe … we have a week between now and your next appointment, and we would like to do something to give you some relief from your symptoms. Many different kinds of tranquillisers and similar pills have been used for conditions such as yours, and many of them have helped. Many people with your kind of condition have also been helped by what are sometimes called ‘sugar pills’, and we feel that a so-called sugar pill may help you, too. Do you know what a sugar pill is? A sugar pill is a pill with no medicine in it at all. I think this pill will help you as it has helped so many others. Are you willing to try this pill?”

They got good results. Go figure, or rather: go buy shares in the homeopathy industry. Sugar pills are the future, if only there was a way to give them with integrity, and a straight face.

· Please send your bad science to bad.science@guardian.co.uk

References:

A good place to read about Moerman’s stuff on ulcers and the rest is in this paper, which most of you with Athens logins should be able to get (I know, I’m sorry, information wants to be free, it’s criminal).

Making space for the placebo effect in pain medicine

Daniel E. Moerman, Anne Harrington

Seminars in Pain Medicine

Volume 3, Issue 1, March 2005, Pages 2-6

dx.doi.org/10.1016/j.spmd.2005.02.008

The antidepressants’ increasing placebo effect is from Walsh 2002, and is free access.

Placebo response in studies of major depression: variable, substantial, and growing.

Walsh BT, Seidman SN, Sysko R, Gould M.

JAMA. 2002;287:1840-1847.

jama.ama-assn.org/cgi/content/full/287/14/1840

And lastlly, basically I rule the internet, because to my total astonishment I have found an online version of Park and Covi’s classic 1965 paper describing an open and honest trial of pink sugar pills, which is a relief, because when I went to read it ages ago I had to go all old skool in the library with paper and my (top tip coming) digital camera, the perfect way to sidestep libraries’ preposterous photocopying charges. Here it is:

An Exploration of Neurotic Patients’ Responses to Placebo When Its Inert Content Is Disclosed

Archives of General Psychiatry April 1965, Vol. 12, pp. 336-345

LEE C. PARK, MD, AND UNO COVI, MD, BALTIMORE

www.leecrandallparkmd.net/researchpages/placebo1.html