Trick Question: Lamictal for Bipolar Depression

GSK manufactures Lamictal (lamotrigine), used for treating bipolar depression. Which drug company sponsored the one unambiguous clinical trial showing that Lamictal is effective for this use?

Answer: Eli Lilly. Here's the story, which I reported in full in my Newsletter in early 2007:

In 1999, GSK published a study showing that Lamictal was effective for treating bipolar depression in its acute (initial) phase. The finding was at best ambiguous, as the study failed on its primary endpoint.

GSK spent the next six years working to come up with a study that would impress the FDA. (The FDA looks for at least two successful trials.) In all, GSK sponsored seven more acute phase trials testing Lamictal for unipolar and bipolar depression. In each of these studies, Lamictal failed to beat the placebo. Predictably, none of these studies was published.

But GSK did come up lucky in two long-term studies showing that, compared to lithium, Lamictal worked better at delaying relapses into bipolar depression. These studies had a major flaw in that the long-term phase only included patients who had responded to lithium or Lamictal during the initial phase of the study. In other words, "non-responders" likely to fail had been weeded out.

Nevertheless, on the strength of these two studies, in 2003 Lamictal received an FDA indication for "bipolar maintenance."

The news was interpreted as an FDA indication for treating bipolar depression, which was clearly not the case. Predictably, GSK did nothing to disabuse patients and clinicians of the notion. Quite the contrary, GSK launched an aggressive advertising and marketing campaign targeted specifically at bipolar depression.

Four North American treatment guidelines, including one put out by the American Psychiatric Association, bought into the hype and came out recommending Lamictal as a first option for treating acute bipolar depression. Ironically, treatment guidelines are supposed to be "evidence-based."

One beneficial result of GSK's efforts was that bipolar depression - which is more prevalent and destructive than mania, not to mention much harder to treat - began receiving the attention it deserved. Lamictal's flavor-of-the-month status also drew long-overdue attention to bipolar II and "soft" bipolar.

Here's where Eli Lilly comes in. In late 2003, the company received a true FDA indication for its combo Prozac-Zyprexa pill, "Symbyax," to treat bipolar depression. Confident its own med would crush the competition, Eli Lilly sponsored a head-to-head trial (with no placebo group) pitting Symbyax against Lamictal under conditions that gave its own drug considerable home field advantage.

Get ready for this: On the important measure for bipolar depression, Lamictal and Symbyax ended up in a virtual dead heat. Not only that, those on Lamictal had way fewer side effects.

Here's how Eli Lilly spun the study (published in 2006):

"[Symbyax]-treated patients had significantly greater improvement than lamotrigine-treated patients in change from baseline across the 7-week treatment period on the Clinical Global Impressions-Severity of Illness scale ..."

The best way to explain the spin is this: If Eli Lilly were AIG, they would be reporting record profits.

So, there you have it: The story of how Eli Lilly came to sponsor the one unambiguous trial showing that GSK's Lamictal works against bipolar depression.

A couple of follow-ups:

Following the revelation of the unpublished GSK studies, in its new bipolar treatment guideline due out next month, the American Psychiatric Association will no longer be recommending Lamictal as a first treatment option for acute bipolar depression.

In the wake of Lamictal going generic last year, GSK no longer heavily markets the drug.

Further reading from mcmanweb:

Treating Bipolar Depression

At the 2008 APA symposium, Robert Post MD of Penn State advised: "We have to change the way we practice this illness."

Back in 2001, in a survey by the Stanley Foundation Bipolar Network, Dr Post and his colleagues did some counting of their own. Their tally revealed that, despite the fact that mania gets virtually all the attention, bipolar patients are depressed three times more than they are manic or hypomanic.

Knock me over with a feather. Now if we only knew how to treat bipolar depression. ...