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The Birth of Lamotrigine

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Richard Weisler tells the tale of science and serendipity that lead to his discovery of lamotrigine for bipolar depression 30 years ago. He shares a few dosing tips, and touches on how he works with patients and their families. Plus, the word of the day: Gramophone Syndrome.

Published On: 1/25/21

Duration: 23 minutes, 30 seconds

Rough Transcript:

Today, Richard Weisler shares the tale of science and serendipity that lead to his discovery of lamotrigine for bipolar depression 30 years ago.  

Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report. And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

Kellie Newsome: On April 3, 2003 Dr. Russell Kat sat down at his desk at FDA headquarters to review a proposal to approve lamotrigine in bipolar disorder. It was not a straight-forward case. GlaxoSmithKline had submitted 12 trials, but lamotrigine only had a significant effect in two of them. Among the disappointing results were studies in acute mania, acute bipolar depression, acute unipolar depression, and long-term trials in rapid cycling bipolar disorder. But Dr. Katz knew that negative results like this were common, even in drugs that were known to work. And lamotrigine, he reasoned, had to be titrated slowly over 4-6 weeks before reaching an effective dose, so might be forgiven for failing to make a difference in short-term studies that lasted only 7 weeks.

In any event, the manufacturer was only asking for approval as a maintenance drug, and it was in those studies that lamotrigine shined.  Their hopes rested on the two maintenance trials, each lasting a year and a half, and together involving over a thousand patients. Over that year and a half, lamotrigine helped patients remain well more than twice as long as placebo (197 days vs. 86 days). Its strongest effect was against depression, but it also helped prevent mania and hypomania. Dr. Katz voted to approve, and on June 20, 2003 he sent a letter to the team at GlaxoSmithKline announcing the news.

Dr. Aiken: But lamotrigine’s origins as a mood stabilizer began long before, at a medical conference in Japan, where psychiatrist Richard Weisler learned about lamotrigine’s effects from European neurologists who were attending the conference. Lamotrigine was not yet available in the US, but Dr. Weisler had a sense that the drug might work in bipolar disorder. He wrote to the FDA to ask permission to import the drug for compassionate use and tried it out in two of his patients with refractory bipolar depression. Both experienced remarkable recoveries, and one of them quickly relapsed when the supply of the drug was delayed by US customs. 

Usually these kinds of medical discoveries have their origins in animal models, laboratory studies, and academic research teams. But Dr. Weisler did all this as a solo private practitioner. His observations quickly caught the eye of the research community, and with their help he convinced GlaxoSmithKline to test lamotrigine out in an ambitious series of 12 controlled trials. We caught up with Dr. Weisler at his office in Raleigh, NC.

Dr. Aiken: What was it about lamotrigine that made you think it might work in bipolar disorder?

[Weisler’s answer]

Kellie Newsome: In the 1970’s, Robert “Bob” Post came across an explanation for recurrent seizures called “Kindling.” Neurologists had noted that the more seizures a patient had, the more likely they were to recur and the more easy they were to trigger. He saw a similarity in psychiatric disorders, first in drug addiction and then in bipolar disorder. The first 1-2 episodes of bipolar disorder tended to be induced by stress, but after that they seemed to come on autonomously, without any relationship to triggers. It was as if tracks were being laid down in the brain, sensitizing the patient to more and more episodes. This lead Dr. Post to test carbamazepine as a mood stabilizer, work that Dr. Weisler would pick up later in the early 2000’s to get carbamazepine approved. So when Dr. Weisler met with epilepsy experts in Japan, his eyes were open for new anticonvulsants that might tamper the kindling in his bipolar patients.

Kellie Newsome: Dr. Weisler’s second patient was a young health care professional with rapid cycling bipolar disorder that had not responded to multiple antidepressants, mood stabilizers, and novel therapies like lightbox and Synthroid. This patient had a significant recovery on lamotrigine. It was lucky that his first two patients responded so well, and it was also fortuitous that manufacturer of lamotrigine – Burroughs Wellcome (which later became GlaxoSmithKline) – was a short drive from his office in North Carolina’s Research Triangle Park.

Dr. Aiken: Soon after your report the manufacturer launched 12 trials of lamotrigine in mood disorders, including a few long term studies. Is that unusual to invest so heavily in an unproven treatment?

[Weisler’s answer]

Dr. Aiken: When the results came in, only the maintenance trials had a clear, positive signal. How did the profession react? Was there a sense that lamotrigine had missed the mark or id people grasp the importance of long-term results in bipolar disorder?

[Weisler’s answer]

Dr. Aiken: In practice we usually evaluate medications based on their short-term results. But lamotrigine’s real benefits may not show themselves for months. How to you know if it’s working?

[Weisler’s answer]

Dr. Aiken: Serum lamotrigine levels are generally not useful in psychiatry. However, you might consider it if the patient has an unusual response and you have reason to suspect their level is off (e.g., drug interactions or genetic variations at the UGT1A4 or UGT2B7 enzymes where lamotrigine is metabolized). At doses of 100-250 mg/day, serum levels tend to fall in the 2-6 mcg/ml range (Kikkawa A et al, Biol Pharm Bull 2017;40(4):413-418; Douglas-Hall P et al, Ther Adv Psychopharmacol 2017;7(1):17-24).   

Kellie Newsome: Dr. Weisler is credited with the discovery of lamotrigine in bipolar disorder because he was the first to use it there and report on it. But one thing he made clear was that he could not have done this on his own – it took a community of physicians, researchers, and industry leaders to make this happen. He also brings that same sensibility to his private practice, and emphasized to us how important it is to involve the patient’s family and community in their care.

 Kellie Newsome: Dr. Weisler has been in private practice in Raleigh NC since 1980, and holds adjunct professorships at UNC-Chapel Hill and Duke. Through his private practice, he has served as the principal investigator in over 200 clinical trials, including many that changed modern psychiatric practice: carbamazepine, brexpiprazole, quetiapine, and olanzapine in mood disorders, gabapentin and pregabalin in anxiety disorders, Vyvanse and other stimulants in ADHD, bupropion in depression, and several antidepressants in PTSD.

Kellie Newsome: And now for the word of the day…. Gramophone syndrome

Dr. Aiken: Has anyone ever told you you sound like a broken record? In its extreme form, that’s what gramophone syndrome is. This is a symptom seen in Pick’s disease, where the patient compulsively repeats an elaborate story, each time telling it as if it were something new. Here’s how Dr. Mayer-Gross first described the syndrome in 1931:

Kellie Newsome: “Every time a physician or one of the staff came near the patient, he would repeat with correct expression and diction an elaborate anecdote, seeming himself highly amused by it, and could not be stopped until he had told the whole story. After a short interval he would repeat his anecdote as something quite new. There was nothing else one could get out of him. Understanding of speech was almost completely lost. An increased urge to talk, together with poverty of ideation and loss of retention, had produced the symptom.”

Dr. Aiken: Pick’s disease is a type of frontal-temporal dementia, which is the second most common dementia after Alzheimer’s. But unlike Alzheimer’s, frontal-temporal dementia usually begins early, between age 45-65. And it involves more pronounced emotional and behavioral symptoms that may be mistaken for depression at first: profound apathy, emotional blunting, lack of empathy, and changes in social behavior. In the later stages these social behaviors become more extreme, with disinhibition– for example – the patient may disrobe spontaneously in public without any awareness of their nudity. Repetitive, compulsive behaviors are also common, and the gramophone syndrome is one of them. Another common compulsion is extreme over-eating.

Dr. Mayer Gross’s description of gramophone suggests that the patient had little awareness of what they were saying, and indeed deficits of language are common in frontal-temporal dementia, including a lack of understanding words – receptive aphasia, and difficulty in using them – expressive aphasia.

Kellie Newsome: Curiously, broken records were not common in the 1930’s when Dr. Mayer-Gross coined the gramophone syndrome term. Back then, records were made of much sturdier material – shellac – and so his description calls to mind a person who plays an entire track on a record player over and over again. The term “broken record” did not come into everyday use until the 1950’s when vinyl records supplanted their heavier shellac forbearers. Vinyl is softer, and more prone to deep scratches that cause a groove lock where a short section to repeats indefinitely, usually punctuated by a popping noise.

Kellie Newsome: Our online edition features a full review of lamotrigine with practical tips on which patients are most likely to respond, and how to dose it in the old and young, and how to retitrate the medication after a rash. Check it out and use our coupon code PODCAST to get $30 off your first year’s subscription. 

Dr. Aiken: Join us next monday for The Antidepressant Calendar, a patient guide to behavioral activation. The Carlat Report has operated free of commercial support since 2003.

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