September 8, 2009

Unpublished Lamictal Studies Left Us Thinking It Was An Antidepressant

If you cheat on your wife, and later learn she had cheated on you, can you say you cheated because she cheated on you?

An great paper by Nassir Ghaemi, saying-- and this is a quote:

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 realize that we do not know.

That kind of thinking exhausts me.


Thus I was surprised to discover the existence of several negative lamotrigine studies... Of the nine lamotrigine related bipolar disorder studies posted on the website, two were positive and published... Five other negative studies involving rapid cycling bipolar disorder, acute bipolar depression and acute mania have not been published and are only available on the GSK website.  Failure to adequately publish these negative studies led to the creation of a clinical impression that lamotrigine is an "antidepressant," a view innocently expressed to me as recently as last week by an academic colleague.

At this point I need to take a nap.  Ghaemi wrote one of the best books on statistics for psychiatrists; so I'm not defending the hiding of negative studies, but is this man seriously saying that the "hiding" of 2 negative bipolar depression studies is the reason an entire planet of psychiatrists thought Lamictal was an antidepressant when there never were any positive studies saying it was?

This is like Pfizer coming out and saying, "sorry we hid the negative data on Viagra and telepathy."  Ok, what?

In fact, there were already three negative studies about Lamictal as an antidepressant published:  the same three that said it wasn't an antimanic either, but only good for the "prophylaxis of mood states," which is like the rock that keeps tigers away. 

The fact that his academic colleague called it an antidepressant means, simply, that he's an idiot.  No, no, no, I'm not being disrespectful, I mean it completely seriously.  He's an academic.  He's supposed to know what the (only) three studies say, especially since he's teaching it to other people; and he's apparently prescribing this thing thinking that it is an antidepressant based on nothing at all.  Ok, maybe not nothing: based on the word of mouth from other people who didn't read the same three articles.

Does Ghaemi think that the unveiling of negative studies is going to change the behavior of a person who is making it up as he goes along anyway?  It doesn't stop astrologers, does it?


Don't look at me like that.  Five years ago if I stood in front of a bunch of psychiatrists and told them that there was no data for the use of Lamictal as an antidepressant or antimanic they would have condescendingly shaken their heads and told me that Charlie Nemeroff had just been there, and he said...

And if I challenged them to read the studies that I had brought with me to prove my point, they would have told me that of course these were only a select sample of studies, there were other studies showing that it was an antidepressant... and I'd say where? and they'd say well... and I'd say what? and someone would inevitably roll out the "if this is true, how come other [smarter than you] people  haven't said anything? And it would all degenerate into the DMZ of  "well, my clinical experience has been..." 

I have managed to publish quite a few papers; but when I tried to publish papers critical of the existing Guidelines--I had experiences quite similar to Ghaemi's:

The paper was immediately rejected by one of the editors in July 2006, without comment. I asked for specific feedback, and received a letter with numerous complaints, such as what follows: "There is a considerable literature on this specific topic, almost all of which you failed to cite". The editor goes on to note that some of these papers were co-written by the editor, which had "profound effects". He continued: "This failure on your part indicates a naivety [sic] or ignorance of the broader picture....You thus fail entirely to give the paper context...As a psychiatrist, you will appreciate the annoyance any JAMA editor might naturally feel when the manuscript he reads has an abstract written in the New England Journal of Medicine style..." He dismissed the abstract as "classic...pretty much useless," the methods as "wandering and discursive," the results as "incomplete ... trivial...If you had sent us a crisp paper that clearly stated a hypothesis, and a credible way of investigating it; if you'd given us the context, clear methods and adequate statistical analysis; if you had provided the relevant citations, and if your hypothesis and investigation had been on something that hadn't been already documented by others: then we might have been interested. Unhappily, you did not. I hope this will help you in the future. Best wishes."
Here's what you don't know about peer review: it's really peer pressure.


I have been too hard on psychiatrists who thought Lamictal was an antidepressant, or even a mood stabilizer.  They were-- pushed-- into thinking it.  If you only read the abstracts:

Conclusions  Both lamotrigine and lithium were superior to placebo for the prevention of relapse or recurrence of mood episodes in patients with bipolar I disorder who had recently experienced a manic or hypomanic episode. The results indicate that lamotrigine is an effective, well-tolerated maintenance treatment for bipolar disorder, particularly for prophylaxis of depression.
it's possible you might have misunderstood the paper and thought it was good for everything.  Hmm.  Maybe the peer reviewers missed that.


Ghaemi has an optimistic bias: "had we known of these, we would have acted."  No, not in this generation's psychiatry.  If the overuse of Lamictal was due to hiding negative studies, does he think its rapid decline in the past two years has been due to the release of these studies?  Did we stop using Depakote because we all finally read the article from 2000?

They went generic.  That's all.  And it's not the absence of reps that made docs forget about these drugs; it's the absence of "studies" and reviews in all the journals telling us, over and over, to use them.

The problem of psychiatry isn't the hiding of negative studies-- even if they were available, it would make no difference, because we're not prescribing based on science, we're prescribing-- like Ghaemi's colleague-- on word of mouth.  Psychiatry is politics, and we basically toe the party line, no matter what common sense, logic, or even science tell us.

Americans learn their civics from the TV news; psychiatrists learn their psychiatry from their newspeople, too.  Those people are called thought leaders, and they have far more power to drive practice than any amount of data, hidden or not.