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The failure to know what isn't known: negative publication bias with lamotrigine and a glimpse inside peer review
  1. S N Ghaemi
  1. Dr S N Ghaemi, Tufts Medical Center, Department of Psychiatry, 800 Washington St, Box 1007, Boston, MA 02111, USA; nghaemi{at}

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“There is a type of interaction between human beings which proceeds not from knowledge, or even lack of knowledge, but from failure to know what isn’t known.” John Kenneth Galbraith1

The medical literature meets Galbraith’s description. Some things we know, and know that we know. Other things we do not know, and know that we do not know. But perhaps the largest class involves those things we do not know, and do not realise that we do not know.

This latter state of affairs is exemplified by the problem of negative studies. It has become increasingly clear that the medical literature is biased toward positive studies; negative studies are less frequently published.2 Sometimes this may reflect loss of passion, as disappointed researchers file away their negative results. Sometimes it may be systematic, as pharmaceutical sponsors may actively suppress negative data which would adversely impact their marketplace sales. And journals may also systematically reject negative studies—which will generate fewer readers, fewer citations and lower impact factors for the journal—more frequently than positive ones.


Negative studies may provide important information. “Negative” does not mean unimportant, and proving something ineffective is as important, perhaps more so, than proving it effective. To be a good physician, knowing when not to use which medications, as Pinel famously said, is even more important than knowing when and how to use them.3 Drugs that are ineffective might be somewhat harmful; almost all drugs are harmful in some way; thus the risk–benefit calculation is always hurtful for an ineffective drug. Furthermore, drugs which are effective are often not used, since the ineffective drugs are seen as effective, and thus the truly effective drugs, which sometimes have more side effects, are pushed aside. It is as if the princess at a ball, hidden in servant clothes, …

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