Wednesday, March 25, 2009

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. ...

17 comments:

Lizabeth said...

Well, my pdoc has me slowly going on Lamictal(generic version) so I hope it does something. Both she and my tdoc say they have patients on it that are doing well.

The depression is nasty, mostly I am hoping getting my mood stabilized will help me crawl out of it. Then maybe the Lamictal will help me stay out of it. It is my third worst symptom, right after mixed states and anxiety--which kinds of says how bad those can get with Bipolar II, which is what I have.

The SSRIs and NSSRIs I was on before my Bipolar II diagnosis were not exactly stellar either. They were better than nothing, but had draining effects on my creativity and eventually made me want to crawl out of my skin.

I suppose it comes down to the fact that we have no tremendously effective treatment for either Unipolar or Bipolar depression. It is a mental black hole that just sucks energy and sucks in general.

As for the drug companies, this is the one area that makes me a bit nervous about my tdoc. She seems to trust them while I do not. I trust the people actually working to develop the meds are doing their best, but marketing decisions and the resulting propaganda are out of their hands. And I don't trust the people (read bean counters) who usually make these decisions. They have taken no oath to "first do no harm".

Anyway, I hope you don't mind my ramblings but this column scared me because I am going thru a lot with essentially no helpful meds on board. My hopes there are in the Lamictal--so I'll continue to hope I'll get lucky with it.

And my cell phone still can't launch the space shuttle.

John McManamy said...

Hi, Lizabeth. I think it's safe to believe your pdoc on the value of Lamictal. Clinical wisdom and patient results trump any study data - I heard this from two different psychiatrists at a symposium on treating bipolar depression. I've also heard clinicians swear by Lamictal. Often, study data is incapable of verifying what people actually see with their own eyes.

And of course the evidence is pretty strong now that antidepressants are not all that helpful - and may be harmful for bipolar - which is why getting the correct diagnosis is so important. Again, clinical wisdom and patient results may contradict this, but in your case it sounds like antidepressants weren't right for you.

At the very least, Lamictal (or another mood stabilizer) will bring your cycle under control, which lessens the risk of you cycling back down into another depression.

And you absolutely right about drug companies behaving badly and stupidly. I will have a blog piece on that probably today.

So, by all means be skeptical. Healthy skepticism is our best ally. But so is hope. Be hopeful, too.

And don't worry about rambling. You're not rambling. Your comments are very useful, so please keep posting ...

Anonymous said...

I am on 175 mg of lamictal and I just went on a slow taper off of Lexapro. I have been on SSRI's since I experienced my first major depression at 20. Around 30 I was told I was bipolar (I was in a hypomanic state. I blew the guy off) Many years and cycles later I saw the light when my brother was diagnosed with bipolar I. My husband could not afford my spending sprees. I went to the Psych. I was on Lexapro at the time and I was rapidly cycling throught periods of being ADHD and Hypomanic. My psych started me on Lamictal. I became so stable! Later I still had horrible periods of anger and rage and he prescribed Ativan to help. It did. I could think before yelling. And then.. I decided to wean myself off Lexapro due to the SSRI stigma with bipolar. After all, I had been misdiagnosed! 3 months later I have gone from hypomanic to mixed and now to depressed. Help! Will lamictal help at a higher dose? Or is this a wait and see mode. I am skeptical about all of these drugs. Can lamictal pull me out and up to less mood swings and less depression? AND was I doing the right thing by getting away from SSRI's after all the hypomanic episodes? They sure felt better than this! But I could not afford them. Does Lamictal have the power?

Thanks again for all the info on the drug studies. Susan

John McManamy said...

Hi, Anonymous. Meds work differently for everyone. And we are all unique. So individual internet medical advice - besides being illegal - is dangerous.

As a general rule: A mood stabilizer is your backbone med if you have BP. A mood stabilizer works to get your cycle under control, and when that happens you are less likely to cycle into depression and (hypo)mania.

The good news: It sounds like you are on the right track. You have had some success with the Lamictal. Keep working with your pdoc at refining your meds cocktail.

Anonymous said...

My very cautious pdoc is taking his careful time with assessment, but told me he is thinking of starting me on Lactimal. I like the idea that it is less likely, from what I glean, to cause weight gain (I have a battle with my weight and a past eating disorder) and that it can help with my migraine symptoms.

Lots of times I feel I don't need or want meds, but then I sit in a bone-sucking depression as I am now and it's hard to be patient waiting for a way out. Anti-d's are not a good story with me. I sure hope this will work.

Thanks for this site - it's becoming a 'touch stone'.

Anonymous said...

** Lamictal ( I spelled "Lactimal" above) - is there a med for reversing letters ? I need one. Oh well - right letters, wrong order ... such is my brain.

Louis said...

I have titrated from .25-.50 in 2 week intervals now on 100 mg, I feel less anxious,better concentration and hopefully my mood and depression will continue to improve only side effect is a little fatigue in the beginning, lamictal while maybe not perfect for everyone has been very good for me, no rash. I would encourage someone troubled with depression, anxiety and mood problems to listen to there pdoc. Thank g_d, and best to all.

Anonymous said...

Anonymous,

I have gone through a similar experience as you. I was very depressed and put on lexapro. It seemed to lift my depression and then i became manic. I was put on lithium which i hated. and then on lamictal. at first it lifted me out of depression a little but then it just seemed to keep me from having ups but i was still depressed. I then added an antidepressant to the mix because that seemed to work before i went manic. It has helped me a little and i think i am making progress on getting the right combo. My problem is that when i move up on the lamictal my depression seems to get worse so i am stuck right now. I am scared to go on higher doses of lamictal because it will take a lot out of me and it is not like i have a few months to test it out. I like hearing other peoples experiences, not all those statistics. They dont really speak to individuals. Anybody who really has bipolar with severe depression please share your experience. THanks

Anonymous said...

I cannot comment on severe depression with bipolar but can share that a low dose of Seroquel has helped me to be in touch with reality. I had been on 150 mgs. of Lamictal and also Lithium Orotate plus supplements for a couple years before the Seroquel was added. Lithium Orotate can be ordered on-line and it doesn't have the side effects of Lithum Carbonate. The Orotate takes the Lithium directly to the brain and so only a small dose of Lithium is required. We added 25 mgs. of Seroquel in August of 2008 and increased it to 37.5 mgs. last April. I don't believe that I have to change the world anymore which is really nice. I had treated myself with natural rememdies for four years because I started reading about them and thought they may help me as they did others. I was diagnosed with manic depression in 1975, soI've dealt with BP for a long time. Treating myself was four years of instability at times and much grandious thinking. I am thankful for the medication that I am now taking.

Anonymous said...

interesting that depression can be awakened by taking a med. having a diagnosis of bp is giving me trouble managing my life. Being talented and loved and having wonderful support all of the time is, right now, too much for me to appreciate. so, after realising that it must be the increase of my lamictal that was making me very depressed i could kick myself for not seeing it sooner. i wouldn't have suffered so much. I don't feel any better but i will see my doc tomorrow and not listen to "well, if anyone can handle this, you can." He's right, but with lots of help.

Anonymous said...

After taking Lamictal now for a few months it seems that for the first two or three weeks at each dose, i improve and then sprial back down into a nearly suicidal depression and then my pdoc increases it again and i feel better again for a few more weeks.. I take seroquel at night and lamictal in the am. Am wondering if this is normal until we find the right dose or if this may be an indicator that something is wrong. It also made me rage, I mean ballistic and now I take small doses of xanax as needed, just enough to calm down but not so much that i can't work. I have major unipolar depression with many family members that have severe, even non-medicatible (sp) bi-polar I. Without meds at all I am not functional and still teeter between sick days and work days as some days I just can't bear the thought of facing the world. Any advice?

Anonymous said...

I AM SO RELIEVED THAT OTHERS HAVE HAD THE EXPERIENCE OF SPIRILING BACK INTO DEPRESSION AFTER A FEW INITIAL WEEKS OF FEELING WONDERFUL AFTER TAKING LAMICTAL. IT ALSO HAS GIVEN ME EXTREME TENSION, AND EVEN 2 SLEEPING PILLS AT NIGHT WILL ONLY KEEP ME ASLEEP FOR A FEW HOURS. SEEMS THAT I AM HAVING A BAD EXPERIENCE WITH THIS DRUG.

AndrewMunster said...

I was on 300mg of Seroquel and 300mg of Lamictal. I find the Seroquel on its own works well but the combination is sedating and I spend most of the day popping Ritalin to wake up. I have always had a severe problem staying asleep so the Seroquel was amazing for that as well. The Amphetamine thing is funny because the Seroquel is stronger than them so I can still fall asleep.
The Lamicatl changed my life but only half way. The rest of the work I need to do myself and work on my DBT skills. Drugs help but being aware of your behavior helps a lot more.

Lizabeth said...

This is strange, updating myself. I never got to find out if Lamictal worked or not. I was having so much trouble with mixed moods that my pdoc added Geodon which promptly turned around and ate my brain. I was terrified all the time, I could barely speak two slightly coherant sentences and I could not write at all. I was a BIG emergency in my pdocs office. She spent over an hour with me and I landed in the hospital. The pdoc there was brilliant but he did change my whole combo. So bye, bye Lamictal---but I hope its working for others.

Anonymous said...

Can someone please, please help me? I am really feeling depressed and extremely hopeless. I recently stopped lithium and started on Lamictal for my Bipolar/Depression. Well, I could care less about life & feel as if it was not for me having to raise my gorgeous son, I would give up on life completely. I started feeling this way about a week into taking Lamictal. I really would love to hear that it will pass, but what if it doesn't? I am very scared and am at the end of my rope trying for 20+ years to find something to help my mental condition. Thanks so much for listening and any advice would be so greatly appreciated! Sue

John McManamy said...

Hey, Sue. Lamictal is a miracle med for a good many people with bipolar depression, even if the studies do not bear this out. But you need to give the med a chance to work. For safety reasons, it takes six weeks for docs to prescribe full-strength doses. And it will take about three or four weeks before you start noticing any change.

Unless there are extreme side effects, do not quit on the Lamictal. Give it a chance. In the meantime, do what you can to get out of the house and into the fresh air and get your sleep regulated.

I'm not going to tell you to stay hopeful - you're too depressed for that. Focus on getting through the day and know you are not alone.

MRose said...

Lamictal is not a good drug for everyone. The side effects out way the good. I went to the hospital yesterday with my throat closed and my tongue swollen. Come to find out if your allergic to sulfa you should not take this drug. Why do they have you fill out those papers if they don't look at them. I'm really mad. Lamictal can cause insomnia and they gave me a pill to sleep. Does this make sense?