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How do you start lamotrigine? Do you use the standard titration? As you know, that’s 25 mg for 2 weeks, 50 mg for 2 weeks, and then weekly increases by 100 mg until response, problems, or a dose of 400 mg. Is that what you do? When would you do something else?
Hi! Jim Phelps here for the Psychopharmacology Institute. For patients who can handle some pill chopping, can you go slower than the standard approach—say, 12.5 mg for a week and then increasing weekly by that amount to 50 mg? It’s the same net result at 4 weeks, just with a little slower start and a slightly smoother increase. Will that lower the rash rate?
Mind you, we’re not talking about the really dangerous rashes here, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, or other drug hypersensitivity syndromes. We’re talking about the benign rash, which has a published rate of about 10% using the standard titration. This benign rash can halt a lamotrigine trial that might otherwise have led to effective monotherapy with no significant long-term risks. So, if you could lower the rate of the benign rash even just a little bit without significantly slowing the titration, that would be great. Is that possible?
Well, now, we have some real-life data on this question. Dr. Tomoyuki Nakamura and colleagues looked back at the records of 300 patients, about half of whom started at the standard rate while the other half started at slower rates, such as I just described, or even slower, such as 12.5 mg for 2 weeks, then 25 mg for 2 weeks, and so on. This is basically halving the standard titration doses or doubling the duration of each step—or sometimes both. The question is, did patients on the slower schedules have a lower rate of the benign rash? In the standard titration group, the rate of benign rash was 16%, whereas the rate in the slow titration group was almost two-thirds lower at 5.8%. The rate of any adverse effects, such as nausea or headache, was also cut in half from 20% to 10%. Two other research studies of slower than standard titration had similar results. All 3 papers conclude that we should start lower and go slower than the standard titration.
But how much slower? It already takes 6 weeks to get to 200 mg, and this has led some practitioners to think that lamotrigine is too slow to bother starting on in an inpatient unit, for example. That’s ironic because I know that some of those same practitioners are starting antidepressants, which we routinely describe as taking up to several weeks to have benefit. But lamotrigine is no slower than antidepressants. As you’ve likely seen, when lamotrigine works well, there’s often evidence of some response at 50 mg and sometimes even a hint at 25 mg. In a randomized trial of lamotrigine vs olanzapine–fluoxetine combination for bipolar depression, lamotrigine response was not slower. Although it never worked quite as well, the rate of improvement was the same despite lamotrigine being titrated whereas olanzapine–fluoxetine combination was not.
So, carrying this new paper’s slow titration idea a step further, I recommend increasing to 75 mg at week 5, 100 at week 6, 150 at week 7, 200 mg at week 8, and halting the increase at any point if improvement is substantial because for many patients there is a sweet spot at around 150 mg with full benefit but no word-finding problems.
Three more thoughts. First, lamotrigine now has multiple case reports of inducing a switch into hypomania. Dr. Nakamura and colleagues included this as a potential adverse effect after seeing 1 instance in the 300 patients they reviewed. Second, for experienced pharmacologists, a benign rash need not be the end of lamotrigine. In an important review, Dr. Chris Aiken summarized 27 cases of rechallenge with lamotrigine after a treatment-ending rash, some of which were severe, like lip blisters with fever and adenopathy. In this paper, cautious re-exposure was successful in 22 of 27 patients with no cases of Stevens-Johnson or TEN.
Finally, I’ll pass along this strategy suggested to me by a neurologist with several decades of experience. If a patient calls and describes a rash that is not on the face and with no systemic symptoms or malaise—just a morbilliform rash on arms, leg, or trunk—lower the dose a step back down the titration and have them leave a voicemail every day describing the rash and any other symptoms. If no worsening is described, call them back and authorize another dose until the next day’s report. If the rash worsens, stop lamotrigine. Most often, it will disappear over a few days and then you can continue at that slightly lower dose for a week or so and then resume titration by smaller, slower steps.
In conclusion, for patients who can handle pill chopping, make 12.5 mg your routine starting dose. If they can tolerate a 7- or 8-week ramp to 200 mg, take that time. With this approach, you’ll see fewer benign rashes and less often have to consider halting a lamotrigine trial. For more on this, see that Aiken paper about rechallenging after a rash, which is linked here at Psychopharmacology Institute. It will reassure you.
Abstract
Purpose: Lamotrigine (LTG) is used for treatment of mood disorders, but it is associated with the risk of rash occurrence in the initial administration phase. Although slow titration reduces this risk, its effectiveness in the treatment of mood disorders has not been verified. The effects of titration method on the safety and effectiveness of LTG for the treatment of mood disorders were examined in this study.
Methods: This retrospective cohort study included 312 patients with mood disorders who underwent initiation of LTG therapy. Data regarding baseline demographics, titration schedules, concomitant medications, and time to and cause of discontinuation of LTG were collected. A multivariate analysis was used to evaluate the effects of the titration schedules. The 12-month effectiveness was also evaluated.
Results: The 12-month discontinuation rate of LTG was 16.7%. The most frequent cause of discontinuation was development of a rash (47.7%, n = 312). Fast titration (adjusted odds ratio, 8.15) significantly increased the risk of rash development, and slow titration (adjusted odds ratio, 0.29) significantly decreased this risk. The time to all-cause discontinuation was not significantly different between the slow and standard titration groups (n = 303). After 12 months of treatment, the condition of 46.7% patients were rated much or very much improved using CGI-C.
Conclusions: Although slow titration of LTG reduces the occurrence of a rash, it is not more effective than standard titration in the long term. Optimizing the initial LTG titration schedule for patients with mood disorders is challenging.
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Reference
Nakamura, T., Tomita, M., Hirota, S., Matsunaga, T., & Uchimura, N. (2022). Impact of selected initial titration schedules on safety and long-term effectiveness of lamotrigine for the treatment of mood disorders. Journal of Clinical Psychopharmacology, 42(4), 350–356.
Related References
- Aiken, C. B., & Orr, C. (2010). Rechallenge with lamotrigine after a rash: a prospective case series and review of the literature. Psychiatry (Edgmont (Pa. : Township)), 7(5), 27–32. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2882280/
