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Lamictal fails seven drug tests

Posted by cmorhoun on May 9, 2007, at 10:37:12

Anyone considering Lamictal as monotherapy for depression might want to read on

News - Lamictal Fails Seven Drug Trials

Unpublished data shows drug failed to beat the placebo.

Nevertheless psychiatry endorses Lamictal for acute bipolar depression.

A McMan exclusive.

Have you taken more than one antidepressant and still feel depressed?" reads a banner ad currently running on many mental health websites. The ad goes on to suggest that you may have undiagnosed bipolar disorder and to talk to your doctor. The ad is sponsored by GSK, makers of Lamictal (lamotrigine).

A seven-week 1999 GSK-funded study published in the Journal of Clinical Psychiatry found a benefit for treating acute (initial phase) bipolar depression with Lamictal, though the study did fail on its primary endpoint. Nevertheless, the results were encouraging enough for psychiatrists to begin prescribing the drug off-label.

Seven unpublished phase II and III clinical trials spanning 1999 to 2005, however, tell a much different story. According to trial data listed on GSK’s web-based clinical trial register, Lamictal failed to outperform the placebo in trials ranging from seven to ten weeks. Three of these trials involved unipolar depression, two of these three for recurring unipolar depression, considered by many a close cousin of bipolar depression. Two more involved populations with bipolar I depression, another with bipolar II depression, and another with both bipolar I and II depression.

Thus, out of eight studies over a spectrum of depressed patients in the acute phase, only one yielded results worth publishing.

Over the same time, GSK was also working on a different strategy. Here, they got much better results. In two 2003 published trials lasting 18 months, Lamictal proved superior to lithium at delaying relapses into depression in patients with bipolar I with recently occurring manic or hypomanic episodes (while lithium proved superior at staving off relapses into mania). These results proved to be the ticket to an FDA indication. Significantly, the indication was for bipolar maintenance treatment, not bipolar depression, though GSK was allowed to put on its labeling that the findings were more robust for bipolar depression treatment.

In other words, based on the evidence, Lamictal appears to be a med that will "keep you well" rather than "get you well."

Surely, psychiatry would appreciate the distinction. Uh, read on ...

What the Treatment Guidelines Say

This writer reviewed six major bipolar treatment guidelines, all prepared by leading psychiatrists, with input from many more leading psychiatrists. All but one of the guidelines purports to be "evidence-based." The other relies on "expert consensus." In practice, most, if not all, are hybrid documents.

The four North American guidelines give Lamictal an overwhelming thumbs-up for acute (initial) phase bipolar depression. The American Psychiatric Association’s (APA) Practice Guideline published in 2002 advises: "The first-line pharmacological treatment for bipolar depression is the initiation of either lithium or lamotrigine."

The latest edition of the Texas Implementation of Medication Algorithms (TIMA, formerly TMAP), put out by the state of Texas in 2005 goes one better. For treating acute bipolar depression, the algorithm recommends Lamictal (either alone or with an antimanic agent) as its ONLY first choice.

The Canadian Network of Mood and Anxiety Treatment (CANMAT) Guidelines, issued around the same time as TIMA’s latest version, also recommends Lamictal as a first option for treating acute bipolar depression, but includes other choices, as well.

The 2004 Expert Consensus Guidelines, in its Patients and Families Guide, advises that Lamictal is "sometimes considered an antidepressant agent" and that "antidepressants treat symptoms of depression."

Exhibit A in the evidence line-up for these guidelines is the one GSK Lamictal study that produced an encouraging result. The reason everyone knows about this study is because this is the one that GSK published (in 1999). All four of the guidelines above site this study as evidence of Lamictal’s apparent efficacy, though there are two important caveats:

The APA did note that the study only succeeded using the MADRS scale as a measure (which happened to be the secondary endpoint) rather than the primary one (the HAM-D). In other words, the FDA probably would have thrown this study out.
The editors of the Expert Consensus Guideline did note that enthusiasm for the drug among the 47 psychiatrists it surveyed was rather surprising in light of only one published study.
What about all those failed studies? Nary a mention. Almost. The APA did manage to put a positive spin on one of the failed studies by way of an indirect citation from a review article. In addition, the APA (and TIMA and CANMAT) turned to Exhibit B in the form of a small study comparing Lamictal to Neurontin. The APA also cited an open label study in which most of the patients were on other meds.

Time to hear from the English.

The British Association for Psychopharmacology (BAP), in its 2003 Guidelines, citing "limited evidence," recommends Lamictal as a first choice in the acute phase only for "less severe" depression.

The National Institute of Health and Clinical Excellence (NICE) is far less charitable. Its 2006 Guideline states: "The following treatments should not be routinely used for acute depressive episodes in people with bipolar disorder: lamotrigine …"

NICE cites GSK’s 1999 published study as "inconclusive" for efficacy and "unclear" for risk-benefit. The slow dosing schedule for Lamictal (six weeks to get up to full strength) is also an issue with NICE.

In another section, NICE explains its skepticism for industry-sponsored studies: "Such studies are more likely to report results that favor the sponsor’s product than are independent studies. This may reflect publication bias or design bias."

Publication bias? Talk about understatement.


In science, the object of an experiment is to prove one’s hypothesis wrong. In eight clinical trials – seven failures and one partial success - GSK admirably succeeded beyond its wildest expectations.

As expected, GSK was far too modest to broadcast the results. That, of course, is the job of psychiatry.

Which leads to the crunch question: With my illness, a serious depression is not a matter of if, but when. When that time comes, I expect my psychiatrist to recommend the best treatment to meet my needs. This will probably involve a medication of some sort. I do not expect to be handed what amounts to a placebo with side effects. My life may be riding on the outcome and one wrong choice may prove fatal. The problem is, with the best minds in psychiatry getting it wrong, with the APA itself getting it wrong, how on earth can I trust my psychiatrist to get it right?

For free online issues of McMan's Depression and Bipolar Weekly, email me and put "Sample" in the heading and your email address in the body.

Feb 6, 2007




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