Thursday, January 20, 2011

Lamictal: The Strange Tale of the Med with No Clothes

I've published different versions of this story on Knowledge is Necessity and elsewhere. Here's my latest version, part of a the same article I excerpted from yesterday, on mcmanweb ...

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, "nonresponders" likely to fail had been weeded out.

Another point: Virtually all the patients in the study relapsed anyway. It just took the Lamictal patients a bit longer, so the two studies basically proved nothing.

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

Chances are you have heard your doctor sing praises to Lamictal as the magic bullet for treating bipolar depression, even though there is absolutely no scientific evidence to support this. 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." (A more recent guideline put out by the APA finally got honest.)

It doesn't stop there. Enter the competition. In late 2003, Eli Lilly 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.

Part of the home field advantage included a short seven-week trial period. This is because Lamictal requires a slow titration, involving gradually raising doses over six weeks. Surely, Symbyax would outperform a drug not yet out of the starting gate. But - surprise - 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 [Lamictal]-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 (which went belly up in 2008 in one of the biggest financial scandals in history), they would be reporting record profits.

Ironically, the one unambiguous finding in favor of GSK's Lamictal came from the competition.

Take home message: Psychiatrists swallow this type of bullshit wholesale everyday, which then gets passed on to you as medical advice. Caveat emptor.

15 comments:

Willa Goodfellow said...

Too bad the side effects linger after the placebo effect has faded. Meanwhile, I need a new over-hyped magic bullet. I have run out of chemistry experiments again. :-)

John McManamy said...

Hey, Willa. I do strongly recommend placebos. They work just as well as Lamictal, with no side effects. :)

Seriously, we have both investigated these issues backward and forward. We both know the chemistry experiment is not the answer, or - at best - the answer to the wrong questions.

In my case - there is no med for my depressions. I'm on my own. There are meds for slowing down my runaway brain. So the question I ask is how much do I want my brain slowed down and at what cost?

Our docs err on the side of over-sedating us - to a ridiculous degree. I err on the side of making a social embarrassment of myself on occasions and occasionally over-reacting to my world. I regard this as a small price I have to pay for having a clear brain that delivers for me 99.9 percent of the time.

Most doctors would limit my brain to 50 percent operational capacity in turn for being a bit quieter in public. Thankfully, I have had good luck in working with docs who have been committed to keeping me 90 percent operational - slowed down but mostly in control.

So here's the way I frame my question: I'm crazy. How much of my craziness am I willing to risk putting on display? At least that way I can do a rational risk-benefit analysis. Then it becomes a matter of HOW MUCH of a slow-down med I want to be on rather than WHICH full-strength med.

If I were to ask a different question along the lines of WHICH med, I would get the wrong answer. NONE of them would work, based on any question I would ask.

I could go on and on. I know we've been both grappling with the same issues and I want to hear more from you on this.

Anonymous said...

So where does this leave someone like me?

I've been dx'd with recurrent depression. I've been through various antid's over the years but have remained on Cymbalta for almost a year and a half because it works...kinda' sorta'.

About 6months ago the Pdoc added Lamictal to address a little bit of cycling from deep black to normal every few weeks. No hypomania from what I have ever been able to tell but a few times I've wondered.

Your last two articles asset antid's are only a smidge better than placebo (maybe worse if there is any bipolar) and Lamictal has little evidence to support it's effectiveness.

So what are the alternatives?
- Other antiseizure meds used for bipolar. How effective are they?
- Atypical antipsy's...No thanks.
- Lithium...Mmmaybe.
- Nothing...I've considered it.

I've been reading your column for two years and I've heard the theme before that psy meds leave a lot to be desired. I believe it myself as I've never noted anything but a marginal effect at most.

For me, it's not a matter of choosing how much crazy I wish to display to the world. I'm great at faking normal. However, it's a matter of avoiding those deep black moods that shut me down.

I'm not asking for a reco or diagnosis here but simply asking a rhetorical question. If these things don't work, then what?

John McManamy said...

Hey. Anonymous. I hear you. By all means stick with the Lamictal. It may work for you - and only you matter.

The question we seem to be asking here and elsewhere is WHAT works rather than WHAT MEDS work. For me, it's mindfulness (mind watching the mind), managing stress (such as stopping to smell the roses), and sticking to a regular sleep routine. These are my big three.

Then there's diet and exercise and support and a zillion and one other things. Meds are way down the list. They were at the top of the list in the beginning. but over the years the emphasis changed.

Our docs seem to think we need to remain on high doses forever. Very few in my experience can function well on high doses.

But you have to find what works for you. When you do, please share. We all learn by sharing.

Anonymous said...

Hmmm... good timing. I just started Lamictal after trying all the faves like Lithium, Seroquel, Abilify, etc. I was diagnosed in Sept w/ BPII and have been on a drug roller coaster since. I'm glad to start Lamictal (at least I was) as I've been feeling so sluggish and all. My big concern right now is my job... I've been on medical leave for 7 months and am pretty sure I'll be going back soon. My job is extremely stressful, high vis, constantly moving goal line, etc. I just don't know if I'll be able to do it. I'm single and need the income. Oh, the other thing that I LOVE about this is that my creativity has reached heights I never dreamed possible. I sure don't want the medication to blunt that. Are there others out there who have insight in the job thing and the creativity thing?
Thanks for the site, John. :-)

Moira Wait said...

That med Lamictal, the Empress, looks like she wore no clothes for these studies, but for her Dolce & Gabbana sunglasses. lol

What do you know about Lamictal + lithium in combination?

Anonymous said...

Re: Previous question about creativity.

"Touched with Fire: Manic-Depressive Illness and the Artistic Temperament" by Kay Redfield Jamison

"Exuberance: The Passion for Life"by Jamison

And of course the grandaddy of all books bipolar:
"Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression, 2nd Edition" by Goodwin & Jamison.

Jake said...

I have dealt with several major depressive episodes over the past decade, and as a result have been put on various SSRIs and such during that time. At one point, approx. 7 years ago, I was diagnosed BPII. As a result of this diagnosis, I was medicated with Lamictal for several years, and while I can't say anything has ever worked more than marginally well for me, I do believe it had some positive benefit.

Last summer I began seeing a new doctor and we discussed the possibility that the BPII diagnosis was incorrect and I slowly came off the Lamictal, followed by tapering off Effexor, which I wanted off for other reasons.

Long story short, this past fall I saw myself slowly slide deeper and deeper in to another depression which I am currently still battling through. I was put back on an SSRI (prozac this time), which I have been on for about 8 weeks now, with what I would characterize as producing a slight (if any) improvement. I see my pdoc again next week and admit I am quite tempted to ask to try Lamictal again, despite all the reservations your article describes quite well.

I very much find myself stuck between, on one hand, hating the pharm companies for the influence they have and their ulterior motives, and on the other hand, being desperate for any sort of improvement and thus hoping I'm just one of the lucky ones this particular drug works for.

GJ Gregory said...

I lean towards the manic, rather than depressive side. However, I do suffer depression, usually seasonally triggered. Lamictal seems to help that. But more importantly for me it emerged as a powerful stabilizer. Pre-med I was explosive, and while not directly dangerous to loved ones, very dangerous in terms of fall-out from a rage. It is a wonder drug for me, it saved a marriage, probably my life, made it possible for me to be a passable father, and allows me to work and be productive. While I won't rule out the placebo possibility, I seriously doubt that in my case. Other meds made my condition worse.

You posed the question "WHAT works rather than WHAT MEDS work." Prior to medication I couldn't answer that, I had no comprehension of "normal". I now can clearly comprehend and understand my moods, and think there may be a day I can leave medication with enough self-awareness to adequately cope. It wouldn't be remotely possible without today's use of Lamictal.

Other's results may vary.

Anonymous said...

I can't take Abilify or any of the other related meds in that arena. I had the worst side effects EVER on those. I will never go back there again.

I was out of my mind CRAZY on just anti-depressants. My doc. and therapists think I was a depressive that got pushed over to bi-polar lite from repeated exposure to anti-depressants.

Personally, I think I had bi-polar lite lurking in my background all along. Family history doesn't help either as there is all kinds of crazy on both sides of the family.

I hate that I'm on as many meds as I am but I wouldn't go off them for all the money in the world.

Lamictal helps, but I can't do it alone. I have to have an anti-depressant.

Everyone is different. It's like a poke in the dark. I hate that.

Sometimes your bag of tricks fail you. Sometimes I have to push myself harder. Beats the alternative!

Natasha Papousek said...

Hmm. My Dr. just prescribed Lamictal. Giving it a try. Guess I'll try that grain of salt, too.

Anonymous said...

FDA notified healthcare professionals and patients that Lamictal (lamotrigine), a medication commonly used for seizures in children two years and older, and bipolar disorder in adults, can cause aseptic meningitis.
http://bipolar.about.com/b/2010/08/13/rare-meningitis-warning-on-lamictal.htm

Stevenson said...

I'm bipolar with severe depression and anxiety attacks. I've been on Lamictal for 2 yrs. Since then my anxiety attacks have almost stopped. I do not have the rages of anger like I used to. Lamictal has hugely made my life better.

John McManamy said...

Hey, Stevenson. I hear you. A few weeks ago I asked Hagop Akiskal about the discordance between clinically observed good results and the failed studies. He said GSK didn't know how to measure for bipolar. Indeed, there are different endpoints in these studies, as if GSK is hoping to strike it lucky.

So the point is real world experience trumps clinical trials. You are living proof of that. Thank you for you input and please keep posting.

Anonymous said...

15 years ago TP dx ADD- symptoms consistent with this - stopped ritalin because ins would not cover it. I could focus much better taking it and my brain felt much sharper. Now at age 62 family urges this creative nut with supposedly 138 IQ get help with anger and lack of social skills. So saw psycologist for the first time in my life who stated "your brain is like a racing motor" could be ADD, could be bipolar. I had weaned off Lexapro rx'd by TP was not helping. Psychologist said " If you tell the psychiatrist you have mania/racing thoughts taking Lexapro you will be dx with bipolar." As could be predicted the dx was bipolar II and lamictal was rx'd. I fired the psychologist. I have had hives on trunk and most recently on scalp with each increase - was at 150 mg q day - I decreased the dose to 100 mg. This med has not really helped anything but the racing thoughts which I think are due to ADD and I now have anger fits, negative thinking, agitation, no joy in life, problems with confusion, spontaneity and creativity and my mind is not "sharp" like in the past.
I still have ADD symptoms. Have had two visits with my new psychologist in the same large group with the thinking being that I do not have bipolar at all but do have ADD. No meds for this yet. I just want to be able to enjoy painting (art) and playing guitar/singing again and to stop being a social recluse.

Please comment. Think lamictal should be discontinued.