"Not" Research

When my 2 year old daughter Aviva becomes unspeakably tired, she sometimes moans, "I don't want to go to bed!" When she isn't sure what she wants to eat, she often stubbornly insists on being given the "whole thing" and then leaves the "whole thing" on the table, with perhaps a nibble removed. This perverse tendency towards opposites is not just a phenomenon of two year olds. It appears as a kind of systemetized madness in our world in general and in particular in the world of modern medicine. The "No Child Left Behind" act of our waning administration turns out to be an unfunded mandate, leaving behind every child it purports to help. The law governing the timber industry pushed through by the Bush administration which was sold as a way of protecting the environment earned the moniker "The No Tree Left Behind" act by the environmentalists who exposed its hidden agenda, which was to allow an increase in logging on previously protected lands. "Investment" in today's marketplace, as Paul Krugman points out in a recent editorial in The New York Times, often turns out to be joining a kind of "Ponzi economy" where you let the rich steal your money and you end up in bankruptcy court. I sometimes wonder whether we are we the "not" generation?

Modern medicine has been riding under the banner of "evidence-based medicine" for many years now. This is in many ways yet another ironic hoax, however well meaning, that doctors, researchers, and the public have allowed themselves to be taken in by. As usual, it has been exploited fully by those who tend to profit from it, such as drug companies and the research industry itself. Evidence-based medicine all too often turns out to be (you guessed it) stealth advertising. Naturally, evidence-based medicine is being promoted as an antidote to the kind of irrational and misleading information that advertising is famous for. Not! The campaign to promote evidence based medicine has become an example of science becoming not-science, of salesmanship masquerading as evidence -- it is a wolf in sheep's clothing. While this may not be true for all medical research, I find it hard nowadays to pick up a journal and find an article that is free from the "not" wisdom that poisons our times. It is ironic (but perhaps not surprising) in this "information" age, where through the internet, cell phones, i-phones, and blackberries we can rapidly access more information than was ever before imaginable that so much of it seems to be "not" information.

Let's take a guided tour of a recent example of "medical science" that illustrates this point. This "research" article is contaminated by lies, misrepresentation, and distortion -- enough to make the most aggressive salesman blush. Yesterday, a sales rep left me (red flag) a copy of an article recently published in the Journal of Affective Diseases (109 (2008)252-263). The article is entitled "Efficacy and Safety of Quetiapine in Combination with Lithium or Divalproex for Maintenance of Patients with Bipolar I Disorder." The abstract concludes resoundingly with this bold summation: "Quetiapine with lithium/divalproex can provide an effective long-term treatment option for bipolar I disorder to prevent recurrences not only of mania but also depression." Taken at face value, it would appear that this claim should be considered as a tremendous step forward in the treatment of bipolar disorder. Since many of us doctors are too busy to read scientific articles in depth, to say nothing of critically, this take home message may be what we are left with (this, I believe is what the authors hope). Examining the claim carefully, one might reasonably infer that quetiapine, in combination with lithium or valproex is effective in preventing recurrence of both mania and depression in bipolar disorder.

Eureka! If true, this is the answer that researchers have been searching for for decades -- an effective way of preventing the recurrence of manic or depressive episodes in bipolar patients. Shouldn't this make the national news, if it is indeed the case? Not only that, the article implies that this treatment is just one of many "treatment options" that are available that "prevent" the recurrence of mania and depression in bipolar disorder (although these options are not mentioned in the article). Put to rest your worries, patients and families of patients with bipolar disorder, one need not worry about future recurrences of this illness, if only you or your family member take quetiapine with either valproex or lithium. What a relief!

But not so fast! Elsewhere in the article, the authors write that the addition of quetiapine to valproex or lithium actually only "increased the time to recurrence of any 'mood event' compared with placebo plus lithium or divalproex. In other words, you still get recurrences, but it takes on average longer to get them. Well, that's a different kettle of fish! What happened to "prevent"? A close reading of the article reveals that there are also methodologic limitations, which resulted in the exclusion of many patients who could not be excluded if that patient happened to belong to you, the treating doctor, because they didn't fit the research protocol neatly enough.

The authors also highlight in their introduction that the current treatments available for bipolar disease have "significant safety and tolerability issues." Yet in this particular study, they conclude that the "long term treatment with quetiapine plus lithium or divalproex was generally well tolerated." How can this be, since all of these medications (quetiapine, lithium, and divalproex) are examples of the very treatments which the authors refer to in their earlier criticism of the safety and tolerability of bipolar medications? Finally, in a last ditch effort to dust off the safety record of the drug quetiapine, whose reputation they clearly are attempting to elevate, they say that although there were "increases in weight, lipids and glucose with the addition of quetiapine...", "further long term research studies are required to fully assess the consequence of change in [these] metabolic parameters..." In other words, they imply that bad effects should not necessarily be accepted as valid until further research produces evidence that they are as bad as they sound, but the good effects should be accepted without the need for further research to see if they are indeed as valid as they sound. Ahem!

They conclude that the "results from this study suggest that those two combinations [quetiapine plus lithium or valproex] may carry a positive benefit-risk ratio for the long term treatment of bipolar disorder..." Well, why may carry? Why not does carry? The reasons are clear. This treatment option is not clearly safe. In saying that the treatment may carry a positive benefit-risk ration, the authors implicitly acknowledge that the drugs tested actually may not carry a positive benefit-risk ratio. The word may is one of the most common words I see in medical research articles in the conclusions section. Nobody wants to commit, because, after all, most results are just suggestive, and almost never conclusive. I have found that the only thing one can safely count on in a medical reseach article is that in the body of the text the need for further research will be unquestionably endorsed. And so the research goes on, and on, and on.

I've become so used to these deflating qualifications to research, which are invariably paired with overstated conclusions, that I sometimes feel like I would imagine an experienced chess player feels, who easily finds the weaknesses in his beginning opponent's position. You know they are there, it's just a matter of spending the time, and you will almost surely find them. It's a shame that the authors misstate their conclusions. One can see they desperately want to offer something helpful, and as a result are drawn towards making inaccurate, false or misleading statements. The fact is, in this article, quetiapine did actually decrease the relapse time to the next "mood event." This is a limited but significant finding. If only the authors would acknowledge the full limitations of their work, instead of overstating it, they would not undermine their credibility so much.

Aviva doesn't cause too much trouble juxtaposing her opposites. She may complain about not wanting to go to bed, but she still gets put to bed. Sometimes I wish I could put this misleading research to bed too, but the researchers never seem to sleep.