Thursday, December 04, 2008

Lamictal: Break Out the Shovel

GlaxoSmithKline, manufacturer of lamotrigine (Lamictal), the antiepileptic drug used widely for bipolar disorder, happily hid clinical trial results which found Lamictal was no better than a placebo. Given recent findings about how often pharmaceutical companies selectively push positive results to publication in medical journals while suppressing negative results, this can hardly be considered a surprise. It is nonetheless instructive to examine how the published data on Lamictal paint a much rosier picture of the drug's efficacy compared to unpublished data.

Nassir Ghaemi, a psychiatrist at Tufts University Medical Center, dug through GSK's online database of information, and found that several negative Lamictal studies (studies which failed to show a benefit for Lamictal over placebo on the primary outcome measure) were quietly residing on the site. Why did GSK post such information on their site? Not out of the goodness of their hearts; rather, because they were forced to post data about clinical trial outcomes as a result of a legal agreement. Here's what Ghaemi found in GSK's database:

Acute mania: Two studies compared lithium, Lamictal, and placebo. Both found that Lamictal did not beat a placebo. Neither study was published.

Acute bipolar depression: Three studies were conducted. All three showed negative results. Two were not published. On one study, there was a positive result for Lamictal on a secondary outcome measure, and the results of the study were written to emphasize the positive outcomes, as in stating "Lamotrigine monotherapy is an effective and well-tolerated treatment for bipolar depression."

Rapid cycling bipolar: Two studies were completed; both were negative on the primary outcome. However, one study showed favorable outcomes for Lamictal on several secondary measures. The obviously negative study was not published while the study that showed a number of benefits for Lamictal was published.

Prophylaxis (Prevention of future episodes): Two studies were conducted, both of which showed that patients on Lamictal went longer between episodes than did placebo patients. Both studies were published.

Well, I'm shocked, shocked, that GSK would simply bury a slew of negative data on their product. Who woulda thunk it? So what does this mean for Lamictal? Dr. Ghaemi was interviewed by Dr. Daniel Carlat (of Carlat Psychiatry Blog and the Carlat Psychiatry Report). There were many pieces of Ghaemi's interview that were interesting (see February 2008 issue of Carlat Psychiatry report; sorry, no link available), but the most interesting piece was:
Carlat: My understanding is that you wrote up your discovery of the negative Lamictal data and submitted the paper to some journals. What has been the response?

Ghaemi: I first submitted to JAMA because I knews they were sympathetic to this kind of critique. Their reaction was, "We already publish many papers like this; this is old news; there is nothing new here." They recommended that I send it to a psychiatric journal. So then I sent it to the American Journal of Psychiatry, but they rejected it as well, saying that they were doubtful that this type of negative publication bias was common among other companies marketing medications for bipolar disorder.

Carlat: Do you think there is much suppressed negative data about other drugs?

Ghaemi: It's very hard to get this information. Companies are not required to disclose it. And if they do publish it, they will sometimes delay publication for two or three years, and then publish it in an obscure journal that it less likely to be read.
Ghaemi also did some digging on other drugs used for bipolar disorder and found that negative studies for Seroquel and Abilify were also lurking in the unpublished zone. However, it appears that Lamictal is the worst offender of the bunch. Is it just me, or is anyone else getting flashbacks to GSK's handling of suicide data regarding its antidepressant Paxil?

Thanks to an anonymous reader for helping to track down relevant information on this and an upcoming post on this topic. The forthcoming post will deal with the misleading scientific literature on Lamictal. Key opinion leaders will likely be mentioned. The usual stuff, just on a different drug and plugging in the names of other academics who apparently deemed it acceptable to mislead their fellow physicians about the efficacy of lamotrigine. GSK worked the system expertly and it paid off.

S. Nassir Ghaemi, Arshia A. Shitzadi, Megan Filkowski (2008). Publication bias and the pharmaceutical industry: The case of lamotrigine for bipolar disorder Medscape Journal of Medicine, 10 (9), 211-211


Anonymous said...

why is this surprising to anyone? I thought it was standard practice for pharmaceutical companies to "shop" for good studies.

Anonymous said...

When it comes to selective reporting, perhaps your blog and others should consider holding yourselves to the same standard that you hold the pharma industry to. Here are relevant facts that were omitted from your and other's accounts:
Acute Mania - Both of the lamotrigine acute mania studies were presented at scientific meetings and were described in a review (Goldsmith et al. Drugs 2003) that was issued shortly after the drug was licensed for maintenance treatment of bipolar disorder. BTW this paper contains descriptions of the other study results (e.g. rapid cycling studies) available at the time that GSK supposedly "hid". Of course these data were also submitted to regulatory authorities, including FDA, who made their own decisions as to what should be included in the package insert and have also been freely available on the internet for years now.
Acute Depression - All of the acute depression studies (there were 5 not 3 as you reported) were presented at scientific meetings over the years and were recently published in Bipolar Disorders (Calabrese et al. 2008). Why so long to publish? The paper was rejected twice and took 3 years to get accepted because journal reviewers did not find the data of interest. Regarding the first study published, you state that "On one study, there was a positive result for Lamictal on a secondary outcome measure". Actually there were positive results for lamotrigine on 4/5 secondary outcomes for depression, and on the primary outcome, was positive on the analysis of observed cases and reached p=0.084 on the LOCF analysis (the latter took precedence, which is why the study is nominally negative). Does this constitute proof that the drug doesn’t work? I leave to the educated reader to decide based on the facts that were clearly reported in the paper.
Very hard to get this information? How hard is it to log onto GSK's internet site and research our research? Perhaps a good measure of the extent to which GSK "deceived" the medical community is to peruse literature reviews and treatment guidelines. Try checking out the following guidelines (or even asking the authors about the extent to which GSK cooperated in providing data) and see for yourself the extent to which GSK "hid" these results:
Fung et al. Expert Rev. Neurother. 2004
Sachs et al. J. Clin. Psych 2003
Licht et al. Acta Psychiatr. Scand. 2003
Grunze et al. W. J. Biol. Psychiatr. 2003

You needn’t take my word for it. It just takes a bit of diligence in reviewing and reporting the facts – not just selecting the ones that support your agenda. Perhaps the shovel could also be put to use in your own backyard.

Gary Evoniuk, Ph.D.

Disclaimer - I have provided my name and affiliation in the interest of transparency. However the views expressed above are my own and should not be taken as an official company response.

Monica Cassani said...

thank you so much for this...I highlighted you on my blog...

what is most infuriating about this information is that through my experience for withdrawal from this drug I've learned that hundreds of people have nightmarish withdrawal syndromes coming off a drug that never helped them most likely!!

In fact withdrawing from Lamictal causes great instability and mood swings!!

I thank you very much for giving my readers information that might keep them from ever taking this drug and therefore not having to find out how awful the withdrawal is.

My withdrawal is over, but I'm left with a daunting fatigue that seems to have been triggered by the withdrawal process, another symptom many people have written to me about and commented about on my blog.

Anonymous said...

This is hardly surprising, but I wish this kind of thing got to the public more often, At ALT-therapies4bipolar Yahoogroup we hear more of this kind of thing than most, but we're the choir on this topic.

CL Psych said...

Dr. Evoniuk,

Thanks for your response. I plan to write a followup post that addresses some of these issues. I've read Calabrese et al., 2008 and I realize there were more than 3 studies. I was trying to mostly focus on the Ghaemi article, which discussed 3 studies in its table toward the end of the article. If accurate that the Calabrese et al. paper (2008) was rejected because reviewers found it to lack interest, then the reviewers should be flogged.

And as for your statement: "Does this constitute proof that the drug doesn’t work?" -- looking at the Calabrese et al. (2008) paper, um, I'd say, yes, it seems the drug does very little relative to a placebo for acute depression.

Your statement about GSK's website leaves out one key element; namely, that the website arose out of litigation. Please correct me if I am incorrect, but I believe GSK established the registry site as a result of litigation surrounding suppressed data about Paxil. So it was not a product of GSK's kindness.

But I plan to write more on this in the somewhat near future (next week or so) and I hope you will again chime in. Although my tone may be a little snide at times, I appreciate the input from people who disagree.

Monica Cassani said...

Dr. Evoniuk,

Are you aware of the withdrawal dangers of this drug? There is no mention of it in the literature, beyond the risk of seizure if one cold turkeys. I had to take 2 years to come off of it and I still suffer from horrible fatigue that only started when I began the withdrawal from Lamictal...

I've encounterd many others who have this happen as well, along with other also serious symptoms I mention above...

we know already that GSK has worked as hard as possible to deny Paxil has withdrawal problems...

Anonymous said...

Lamictal is my miracle drug! I've tried so many other options and this is the only one that has been steady and successful in every aspect. Anyone I know that takes this medication shares the same view.

Anonymous said...

My experience with Lamictal as a mood stabilizer has been great. After trying MANY others, this was the only one that did the trick for me.

Anonymous said...

Nice Job! And worth the wait!

I hate Lamictal for the most part, as it is oversold and overprescribed these days by too many of my colleagues.

By the way, congrats for the validation by the GSK rebuttal. You are read and acknowledged!


Anonymous said...

CL Psych:

You are correct that the GSK Clinical Trial Register was required as part of a settlement with the NY Attorney General's office, then headed up by the redoubtable Elliot Spitzer. What few people realize is that GSK was only required to post trial results from studies undertaken after Dec. 2000, but the company took the voluntary decision to post ALL study results for ALL marketed products, including a number of the lamotrigine trials that the company is accused here and elsewhere of suppressing. Furthermore, GSK posts all trial results for all newly marketed products by the time they go on the market, even though the agreement with Spitzer allowed a 10 month grace period.

So...GSK took the voluntary decision to post many of these data (and were admittedly required to post others), the results were also described in the scientific literature (see my previous post) on a voluntary basis, and made available to experts in the field who establish treatment guidelines and make recommendations on appropriate treatment. If this is a case of "hiding" data, then I would suggest that it's hiding in plain sight.

Regarding the use of lamotrigine in acute depression, no the data do not support use of the drug for this indication - although I would suggest that this does not prove it doesn't work. In any case, GSK has never promoted the drug for this use. What the drug is marketed for is maintenance treatment of bipolar disorder, based on data from 2 large, well-controlled, longterm maintenance studies, both of which were positive, i.e. 2/2 studies conducted for this use.

Thanks for the opportunity to comment.

Gary Evoniuk

Disclaimer - I have provided my name and affiliation in the interest of transparency. However the views expressed above are my own and should not be taken as an official company response.

CL Psych said...

Dr. E,

Two trials support Lamictal for long-term usage for those who responded initially. As for the scientific literature on short-term treatment of bipolar depression, I'll be discussing that in a future post.

I'm glad to have this discussion.

GK said...

I share your cynicism with respect to biased reporting of evidence.

However, in our anger about such phenomena, let us not deprive patients of treatments which may in fact help them.

In my opinion, there are many treatments for which there are weak supportive evidence. A recent example is physical exercise--we all want to believe that exercise improves mental health, yet the evidence is probably quite biased, and there are some important recent strong negative studies.

Does this mean we shouldn't prescribe exericse? Of course not! There are many individuals for whom exercise is tremendously beneficial, either subtly or overtly, for helping their symptoms.

Similarly, there are many medications that actually have quite a weak evidence base, such as gabapentin (another drug fallen out of fashion due to negative studies), and perhaps now lamotrigine -- yet I have found numerous individuals for who have found these drugs extremely helpful. Unlike many other medications in the psychiatric formulary, these drugs are usually quite benign, most people tolerate them quite well, and some people are genuinely helped.

Most of the studies -- whether they are negative or positive -- do not look at individual examples within the large groups, to look for specific cases where the treatment has been beneficial.

Also, I come back to another complaint about studies, in which a p value of .05 is considered a standard to judge a finding to be "significant" or not. The p value should be simply stated, and the judgment about significance should be left to the reader. In my opinion, any p value less than 0.5 carries some significance, and is an absurdity--and a betrayal of the motive of statistical analysis, to be a truly neutral judge of meaning in data--that we have such an arbitrary standard of statistical significance, which often hides a clear representation of the data from the reader.

In conclusion, I hear your complaints about lamotrigine studies, these things don't come as a surprise to me--by all means get out the shovel--but let us not throw out treatments that help some people just because we are irritated by bias in the research literature!

soulful sepulcher said...
This comment has been removed by the author.
Anonymous said...

i have endured almost 4 years of chronic bipolar depression, the first 2/3 on SEROQUEL (did not help at all but probably caused type 2 diabetes, elevated cholestol, beginning of cataracts, etc., the other 1/3 on lamotrigine, did nothing for the depression but has given me a low-grade rash, elevated liver enzymes,thyroid defeciency, etc. these are BOGUS MEDICATIONS, why are they still on the market???? DAVID

Anonymous said...

I've found that Lamictal gives me the ability to be aware and take measures to correct an oncoming swing that could easily rollercoaster out of control otherwise. It doesn't take over for me, and still requires intervention on my part to prevent the deep end of down from coming on too fast and too strong, but it does give me the control to be in control. Maybe it hasn't worked for some others and maybe some are looking to take a pill that makes them even-steven happy all day long. Realistically, some of us expect to still have good days and bad days and experience life. As for withdrawals, I loved reading about the ones who said their moods destabilized after they quit taking there meds and blame their meds for that result. And I assume you blame Coppertone when you get sunburned because you stopped using sunscreen too.

monicajane said...

Maybe it hasn't worked for some others and maybe some are looking to take a pill that makes them even-steven happy all day long. Realistically, some of us expect to still have good days and bad days and experience life.

As for withdrawals, I loved reading about the ones who said their moods destabilized after they quit taking there meds and blame their meds for that result.

uh, happily off drugs having good and bad days. drugs often make that sh*t worse.

and those whose mood destabilized after coming off meds include people who NEVER HAD MOOD PROBLEMS before being prescribed lamictal...

explain that before you get all cocky on us.

Unknown said...

I currently take lamotrigine (Lamictal) and have for almost 5 years. It is a miracle drug for the majority of people I know who take it. Like many drugs for bipolar disorder, it is most effective when taken in combination with other drugs AND psychotherapy. The point of medication for mental illness is to make the person stable enough so they can actively participate in psychotherapy, where the greatest benefits are reaped. For all of the people who blogged that it didn't work...have you done intensive psychotherapy to cope with your mental disorder (as well as many of the other recommended means to control moods) or were you expecting to take a bunch of pills and be perfectly stable?

Having worked in the healthcare industry and having done scientific/medical research, I can tell you that in medicine, a p-value doesn't always tell the whole story. Especially in something as complex as mental disorders. If lamotrigine hasn't shown benefit in bipolar disorder, why did the FDA approve it? The FDA requires that ALL of the trial results are presented in the NDA NOT just positive results. In the Lamictal prescribing information this is the indication: Bipolar Disorder in patients ≥18 years of age: maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes in patients treated for acute mood episodes with standard therapy.

When looking at the trials of lamotrigine, there are differences in doses, number of participants, etc. In these studies, the highest dose is 200 mg/day. This is the dose that showed the most efficacy or trended toward significance. I take twice that dose! I also take an antidepressant with it. Without the lamotrigine, I would have full blown mania.

There are also a number of other advantages to lamotrigine compared with other antiepileptic agents such as a better toxicity profile in those who do not get the rash (this proportion has become larger with slower titration), no need to constantly monitor blood levels, efficacy in persons with borderline personality disorder, and seems to have fewer harmful effects on a developing fetus.

I agree with a previous bloger that horrible withdrawal symptoms, especially mood instability, speaks to lamotrigine being an effective mood stabilizer. Also, if people never had mood instability, than why were they taking it in the first place? If they are taking it for epilepsy, there is much anecdotal evidence that epilepsy and mood disorders are linked so this would not be too surprising.

To all of the people who complain about drugs and drug companies, have you ever looked at your part? For physicians, if you were really interested in negative results, then why have the journals not published that which physicians, their subscribers, want? For all patients, what else do you do to stabilize your mood? Exercise? Sleep regularly? Stay away from stress, caffeine, simple sugars, etc? Cognitive-behavioral therapy?

Everyone is so eager to point the finger in our society at everyone else, especially the pharma industry. How many people can honestly say they are not to blame in some small way for the ills of our healthcare system?

Grant Tower, PhD

Anonymous said...

Seems like you've raised some industry hackles with your post. There is one person who readily admits to working for pharma (who seems very testy about your post), another who claims to be a patient with a PhD but sounds remarkably like a pharma scientist and then there's this (this is just a tiny bit of it so you can identify the full comment above):

"As for withdrawals, I loved reading about the ones who said their moods destabilized after they quit taking there meds and blame their meds for that result."

...which sounds remarkably like it was written by someone in a drug company PR department. Hmmm. Nice work. You know you're onto something when the industry people freak out on you and get all cloak-and-daggerish.

Anonymous said...

posts with info on Lamictal

Lamictal Redux

Update from “Lamictal crew” — musings on persistent withdrawal symptoms