LAUSR

Lamotrigine, also frequently referred to by its brand name Lamictal, is one of the most commonly used anticonvulsant medications for the treatment of bipolar disorder. The medication is popular because it has a long-established reputation of efficacy and effectiveness and does not require significant clinical monitoring: there are no annual metabolic labs as with antipsychotics or routine blood level checks as with lithium. In fact, my experience with lamotrigine is it was historically regarded as a relatively innocuous psychotropic agent by clinicians and patients alike—minus the ever-present concerns of rash and Stevens-Johnson syndrome, of course—and for almost two decades has been in frequent use across the world as a first-line option for individuals with bipolar disorder. This made it all the more surprising when the FDA issued a Drug Safety Communication for lamotrigine in October 2020, warning of an increased risk of cardiac arrhythmias, including the possibility of sudden cardiac death for those with pre-existing cardiac disease (U.S. Food and Drug Administration, 2021). I think it is fair to say many clinicians initially missed this memo from the FDA: at the time, we were barely a half-year into the long and taxing COVID-19 coronavirus pandemic, after all. And though lamotrigine is no stranger to safety warnings—over the past 15 years, it has seen FDA warnings regarding immune system reactions, birth defects, and even meningitis—cautionary alerts regarding one’s ticker typically hold a bit more gravity. So, as lamotrigine was certainly one of the last medications on my radar as a possible culprit in abnormal ECGs or sudden cardiac death, I suspect many clinicians shared my experience in that I was thoroughly spooked, especially given how regularly I have prescribed the medication over the years. Though it took a while for clinicians to become aware of the warning, over the past year or so I have seen prescriptions of lamotrigine drop in my local mental health community. The FDA is now requiring a series of safety studies to confirm or counter its warning (U.S. Food and Drug Administration, 2021). That is the bad news. Now the good: given the importance of this medication in the treatment of bipolar disorder, it is reassuring that already we are seeing signs lamotrigine may be safer than the warning suggests. In a brand-new systematic review of the literature, the authors found existing evidence does not sufficiently support the FDA’s warning, stating that when dosed appropriately, lamotrigine is associated at most with a small, non-dangerous widening of the QRS complex (Restrepo et al., 2022). No convincing associations were found between lamotrigine and other cardiac concerns such as Brugada syndrome, QTc prolongation, or sudden cardiac death (Restrepo et al., 2022). The authors recommended that clinicians not instinctively discontinue lamotrigine in reaction to the FDA’s warning, and they also stated that without significant cardiac history, no ECG monitoring is needed before initiating use of lamotrigine in psychiatric patient populations (Restrepo et al., 2022). A newly published observational study of 91,949 users of lamotrigine found no association between lamotrigine and risk of cardiac conduction abnormalities among individuals without cardiac history, and individuals with preexisting cardiac concerns did not see an increased risk of mortality (Christensen et al., 2022). Another 2022 study looking at the pharmacokinetic and biophysical properties of lamotrigine found therapeutic doses of lamotrigine did not result in clinically relevant cardiac conduction abnormalities (Ingleby-Talecki et al., 2022). All in all, the accumulating evidence points in the direction of safety. Despite these compelling reassurances, prescribers of psychiatric medications are now left in the uncomfortable position of recommending lamotrigine to patients in the face of an FDA safety warning. Is there a reason to still consider this agent as a first-line option, given that fact? I think the literature makes a case for ongoing use of the medication, especially for patients without a history of cardiac concerns. It is long known that lamotrigine outperforms placebo in prophylaxis of the depressive episodes that are part of bipolar disorder (Miura et al., 2014; Roosen & Sienaert, 2022). This barricade against bipolar depression is considered lamotrigine’s main strength and has given the medication something of a heroic reputation in the psychiatric arena of bipolar disorder. The 2021 Cochrane Library’s review of lamotrigine confirmed its benefits in preventing bipolar depression, and the most comprehensive systematic reviews and meta-analyses to date looking at the maintenance phase of bipolar disorder demonstrate lamotrigine consistently outperforms placebo and is well-tolerated (Hashimoto et al., 2021; Kishi et al., 2021a; Kishi et al., 2021b). A recent systematic review of affective episodes during the perinatal period, one of the most feared occurrences in bipolar disorder, found