A deep dive into the history, side effects, and efficacy of a controversial drug.
Transcript edited for clarity. - Ed
KELLIE NEWSOME: Lamotrigine was launched for bipolar disorder in 2003, but it was a quiet launch, and since then a few myths have gathered around it as if to fill that vacuum. Today, we will address 4 of them.
Welcome to PsychPearls podcast with Psychiatric TimesTM, the voice of psychiatry. With thoughtful insights into the world of mental health, this podcast provides timely clinical commentary and practical cutting-edge pearls for you and your practice. We hope you enjoy it.
I am Chris Aiken, the Mood Disorders Section Editor for Psychiatric TimesTM and the editor-in-chief of the Carlat Psychiatry Report, and I am Kellie Newsome, a psychiatric NP and the cohost of the Carlat Psychiatry Podcast.
A Quiet Launch
KELLIE NEWSOME: On June 20, 2003, the world had its eyes on the United States’ invasion of Iraq. Some of us were following Martha Stewart’s indictment for insider trading, and quite a few were lining up at bookstores to be the first to buy the 5th installment in the Harry Potter series. But Russell Katz, MD, was busy at his desk on this day at the US Food and Drug Administration (FDA) headquarters, writing a letter to GlaxoSmithKline announcing the approval of their anticonvulsant lamotrigine in bipolar disorder. But the approval was not a slam-dunk. GlaxoSmithKline had submitted 12 trials, and only 2 of them were positive. Lamotrigine did not work in acute mania; it did not work in acute bipolar depression; and it did not work in rapid cycling.
But bipolar disorder (BD) is a chronic condition, and that is where the medication succeeded: in the maintenance phase.
The 2 positive studies looked at lamotrigine in the long term, over 1 and a half years. There, lamotrigine helped patients stay well about twice as long as a placebo.1 Katz knew that long-term studies like this were expensive and hard to come by, but for patients who have to stay on a mood stabilizer year after year it is this kind of data that matters most. So he gave it an indication for delaying new episodes of depression, hypomania, and mania in BD.
CHRIS AIKEN: And that is how lamotrigine was launched. But there are a lot of loose threads in that story that have tangled into myths, and today we are going to unravel 4 of them so you can use lamotrigine more effectively in practice.
CHRIS AIKEN: But first a warning. Lamotrigine is not a panacea. It works in BD, but it does not treat non-bipolar depression. There the studies are mixed: half positive, half negative. It has positive controlled trials in obsessive compulsive disorder, borderline personality disorder, and depersonalization disorder, but those studies are few and small.2 So do not start prescribing lamotrigine to every moody individual you see, because this medicine has one big risk that makes those uncharted adventures unwise: the potentially fatal rash of Stevens Johnson Syndrome.
That rash is part of the reason that lamotrigine had such a soft launch. Early on, the manufacturer decided not to market lamotrigine to primary care practices, and to minimize direct to consumer advertising. The decision may have hurt their quarterly profits, but it helped them stay in the market. You see, lamotrigine was nearly yanked off the market after its launch in epilepsy 10 years earlier. Back then, doctors were starting the drug at 100mg a day, which lead to an alarming rise in potentially fatal Stevens Johnson rashes. The medication only survived when the company was able to show that it could lower this risk through the slow titrations that we use today. Now that risk is around 1 in 3000.3
GlaxoSmithKline was concerned that if they overhyped the drug, then clinicians with little experience in BD would prescribe it to every moody patient they saw, and if they overlooked the DSM in that way they might also overlook the titration instructions, causing a second flare of serious rashes that would cause the FDA to pull the plug again.
KELLIE NEWSOME: And now let us get into those myths. There are 4 of them.
Myth #1: Lamotrigine does not help mania
Myth #2: Lamotrigine does not treat acute episodes of bipolar depression
Myth #3: Lamotrigine is a weak mood stabilizer
Myth #4: It is a good idea to stop lamotrigine when a patient relapses, because it is probably not working
Myth #1: Lamotrigine Does not Help Mania
CHRIS AIKEN: This one is kind of true. Lamotrigine failed in the acute mania trials, and nothing that we have learned about this drug in the 25 years since suggests that it has any role in acute mania. But lamotrigine does help prevent mania, although it is better at preventing bipolar depression than it is at preventing mania. What that means in practice is that you should not rely on it as the sole maintenance medication in patients with a history of severe mania, but it may be used as monotherapy in bipolar II disorder, where the depressions are more common and the manic symptoms brief and mild.
In fact, many bipolar experts see good results in cyclothymic patients, who cycle frequently between mild depression, hypomania, and mixed states. That observation only supported by open-label studies, but hey – there are zero controlled medication trials in cyclothymic disorder so that is as good as it gets.4,5
Myth #2: Lamotrigine Does Treat Acute Episodes of Bipolar Depression
CHRIS AIKEN: Among the 12 trials on Katz’s desk, 5 of them are good candidates for the most disappointing trials in the history of psychiatry. These were the 5 controlled trials in acute bipolar depression, all funded by the manufacturer, and all of them failed. The trials were never published, but most psychiatrists knew about them when lamotrigine was released, and it gave some of us the impression that lamotrigine was a weak mood stabilizer that barely got approved for an indication that was not at the top of the list for doctors or patients.
But we have since learned that lamotrigine does treat acute depression, it just takes a little longer than faster options like the atypical antipsychotics. The problem is that the early studies only lasted 7 weeks, and lamotrigine requires a slow titration that takes 4 to 6 weeks to reach a therapeutic level. Later, lamotrigine did prove efficacious for acute bipolar depression in 2 independently funded randomized placebo-controlled trials.6,7
KELLIE NEWSOME: Wait a minute. You are saying the industry sponsored trials were all negative but the independent ones were positive? That is a first.
CHRIS AIKEN: Yes, and the difference is that the independently sponsored trials gave lamotrigine a little more time. They lasted 8 to 12 weeks instead of 7 weeks. Also, lamotrigine was used as augmentation in these trials – in 1 it augmented lithium and the other quetiapine – but I think lamotrigine can work as monotherapy in acute depression and the real difference here was the timespan.
KELLIE NEWSOME: One reason we think it works as monotherapy is that John Geddes, MD, FRCPsych, Joseph Calabrese, MD, and Guy Goodwin, DPhil, reanalyzed the original 5 negative trials in an independently funded meta-analysis.8 They found that there was a positive signal in the original studies, but they were too small to detect it. When combined together, totaling 1072 participants, lamotrigine had a small effect, bringing about a meaningful response in 1 out of 11 participants. But hey, cariprazine got FDA approval in bipolar depression with the same number needed to treat, and lamotrigine’s efficacy only starts to build at that 7-week mark. If you use lamotrigine for acute depression, you will probably need to wait about a month and a half to see an effect, and, judging from the longer trials, those benefits are likely to keep building over the next 1 to 4 months.
A common strategy then is to start lamotrigine with a faster-acting agent like an atypical antipsychotic, and then slowly taper off the antipsychotic as lamotrigine starts to kick in. This gives you the best of both worlds: lamotrigine has excellent tolerability over the long term, with a low risk of weight gain, fatigue, cognitive problems, sexual dysfunction, or any of the long-term medical problems that show up in the warnings for antipsychotics.
CHRIS AIKEN: One risk we do not think about enough is stroke. Stroke is the #1 cause of death in bipolar disorder, and lamotrigine and lithium are the only mood stabilizers that do not increase the risk of stroke; all the others have some marks against them there.9 I am going to get on a soap box for a minute here and argue that bipolar is not a mental disorder. It’s a physical disorder, and not just because the brain is a physical organ. Heart disease starts 10 to 15 years earlier in individuals with BD, and you can even detect cardiovascular changes in teens with bipolar. Lifestyle may play a part, but I think about all that adrenaline pumping through the veins during mania and mixed states. This is a whole-body illness, and we ought to be thinking about long-term morbidity and mortality when choosing a mood stabilizer, not just relieving acute symptoms.
KELLIE NEWSOME: Are you off your soap box yet?
CHRIS AIKEN: No, I have one more thing to say. The DSM is often criticized for promoting biological psychiatry through its black-box, symptom check-list approach. But to me, it is not biological enough. You could read the whole book and walk away with little sense that these mental illnesses are wrecking havoc on the heart, the gastrointestinal tract, the immunologic and neuroendocrine systems. You would never get that sense from reading Harrison’s textbook of internal medicine.
KELLIE NEWSOME: OK, can we get back to lamotrigine now.
Myth #3: Lamotrigine Is a Weak Mood Stabilizer
CHRIS AIKEN: Yes, and that segues back to another myth about lamotrigine, which is that treatments that are slow to act are not strong ones. This is not how chronic diseases are approached in other medical specialties, which naturally take a long-term, disease-modifying view. You will never see a diabetes study that looks at change on a symptom check-list over 4 weeks. Or take hypertension. Clonidine lowers blood pressure right away, but most physicians prefer a thiazide for hypertension because it lowers the long-term risks of morbidity and mortality.
Individuals with bipolar disorder die 10 years earlier on average, and not from suicide. Kellie, can you read the top causes of death in bipolar disorder10:
Chronic obstructive pulmonary disease (COPD)
Pneumonia and influenza
CHRIS AIKEN: Right, so if you can find a mood stabilizer that reduces those risks, or at least does not increase them, that is golden. Lamotrigine is neutral on all of them, and lithium brings down most of them. Specifically, lithium lowers the risk of heart disease, stroke, cancer, viral infections, and suicide.
KELLIE NEWSOME: But we are getting a bit ahead of ourselves here. I mean, long-term medical risks are important when considering a mood stabilizer, but we also want something that prevents the episodes. Here we have an interesting finding from studies that have compared lithium and lamotrigine.1 Lithium offers better prevention against the manic side, while lamotrigine works better against the depressive side, so combining the 2 makes sense. And one study did that – the LamLit trial – and confirmed that there are indeed additional benefits to combining the 2.3
CHRIS AIKEN: And that is the long-term perspective that we need to take when choosing a mood stabilizer. This does not come naturally in psychiatry. If you work in a hospital, insurance is pressuring you to get the patient better quickly, so lamotrigine is not going to be your go-to agent. And if you work in an outpatient office, ask yourself: When was the last time a patient came in saying “I’d like a medication to prevent bipolar disorder”? In psychiatry, we treat suffering, and our patients want something that will work quickly.
And that brings us to the fourth myth.
Myth #4: It Is a Good Idea to Stop Lamotrigine When a Patient Relapses, Because It Is Probably not Working
KELLIE NEWSOME: In the maintenance trials, lamotrigine delayed the time to a new episode by 197 days, about half a year, vs 86 days or 3 months for placebo. So it is about twice as effective as placebo, but it does not provide 100% protection (no mood stabilizer does). In practice, here is what I tell patients when starting it:
Lamotrigine’s going to have a slow build because you have to raise it slowly to prevent a serious rash. That means you’re going to feel better gradually over the next 1 to 2 months, but on the other hand you are not likely to have many side effects or medicated feelings. And that is a good thing because you are likely to need something long term to prevent mood problems, and this one does not have any major long-term risks. But keep in mind it is not going to prevent all mood episodes, but it will cut the rate of those episodes in half. So instead of having depression, say, every year, it may be every 2 years. But no medication does everything, and there is a lot you can do to raise those odds of success.
Then I talk about behavioral strategies for bipolar and depression. If you are interested in that, we have a separate podcast for patients that teaches these strategies. Search for The Pocket Psychiatrist in your podcast store.
CHRIS AIKEN: A common mistake is to stop lamotrigine when an episode returns, which is a bit like stopping blood pressure and cholesterol medications because a patient had a heart attack. Lamotrigine’s most robust effects are in prevention, and prevention is difficult to measure in psychiatry. You would need a before-and-after mood chart to confirm that the medication is lowering the frequency of episodes as it promises to do. Even then the work is difficult because so many other factors can make mood better or worse. What I look for is improvement in the first 3 to 6 months after starting lamotrigine. If a patient stops it, I watch for worsening over the next 3 to 6 months. And I also listen for something that I have heard a lot of patients say on this medication, particularly those with the frequent ups and downs of cyclothymic disorder.
KELLIE NEWSOME: What is that?
CHRIS AIKEN: They say they still feel the same about whatever problems they were having in life, but the feelings are less overwhelming. They see things in perspective better. And that matches up with what we see in neuroimaging studies of lamotrigine. The amygdala is less reactive to emotionally disturbing images, there is a rise in brain-strengthening BDNF in the amygdala and frontal lobes. Overall, there are volumetric changes in both the amygdala, which react to emotional events, and the frontal lobes, which temper those emotions and help individuals see things in perspective.
KELLIE NEWSOME: That sounds like something we could all use.
CHRIS AIKEN: Hold it there! This medication is not for everyone, and those imaging studies were done in individuals with bipolar disorder.
KELLIE NEWSOME: Always on your soapbox. We will be back with more practical updates on PsychPearls, and you can also catch us every Monday on the Carlat Psychiatry Podcast.
Chris Aiken, MD, is the Mood Disorders Section Editor for Psychiatric TimesTM, the Editor in Chief of The Carlat Psychiatry Report, and the director of the Mood Treatment Center. He has written several books on mood disorders, most recently The Depression and Bipolar Workbook. He can be heard in the weekly Carlat Psychiatry Podcast with his cohost Kellie Newsome, PMH-NP. The author does not accept honoraria from pharmaceutical companies but receives royalties from PESI for The Depression and Bipolar Workbook and from W.W. Norton & Co. for Bipolar, Not So Much. Kellie L. Newsome, PMH-NP, is the cohost of the Carlat Psychiatry Podcast and is also a practicing psychiatric mental health nurse practitioner in Winston Salem, NC, at the Mood Treatment Center. Raised in Tasmania, Australia, Kellie moved to the United States in 1998.
1. Goodwin GM, Bowden CL, Calabrese JR, et al. A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder. J Clin Psychiatry. 2004;65(3):432-441.
2. Reid JG, Gitlin MJ, Altshuler LL. Lamotrigine in psychiatric disorders. J Clin Psychiatry. 2013;74:675-684.
3. Aiken CB, Orr C. Rechallenge with lamotrigine after a rash: a prospective case series and review of the literature. Psychiatry (Edgmont). 2010;7:27-32.
4. Manning JS, Haykal RF, Connor PD, et al. Sustained remission with lamotrigine augmentation or monotherapy in female resistant depressives with mixed cyclothymic-dysthymic temperament. J Affect Disord. 2005;84:259-266.
5. Goldberg JF, Bowden CL, Calabrese JR. Six-month prospective life charting of mood symptoms with lamotrigine monotherapy versus placebo in rapid cycling bipolar disorder. Biol Psychiatry. 2008;63:125-130.
6. van der Loos ML, Mulder PG, Hartong EG, et al. Efficacy and safety of lamotrigine as add-on treatment to lithium in bipolar depression: a multicenter, double-blind, placebo-controlled trial. J Clin Psychiatry. 2009;70(2):223-231.
7. Geddes JR, Gardiner A, Rendell J, et al. Comparative evaluation of quetiapine plus lamotrigine combination versus quetiapine monotherapy (and folic acid versus placebo) in bipolar depression (CEQUEL): a 2 × 2 factorial randomised trial. Lancet Psychiatry. 2016;3(1):31-39.
8. Geddes JR, Calabrese JR, Goodwin GM. Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. Br J Psychiatry. 2009;194(1):4-9.
9. Chen PH, Tsai SY, Pan CH, et al. Mood stabilisers and risk of stroke in bipolar disorder. Br J Psychiatry. 2019;215(1):409-414.
10. Aiken C, Phelps J. Bipolar, Not So Much. W.W. Norton & Company; 2017.