Lamotrigine: Its Role in Bipolar Disorder

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Lamotrigine monotherapy has emerged as a possible treatment for bipolar depression. It is not associated with weight gain and is less likely to cause neurocognitive adverse effects and sedation. Most patients tolerate it well. It does carry a risk of dangerous rashes, but the risk is minimized by slow dosage titration and alert monitoring. The incidence of serious rash may also be less than previously reported (in particular, when faster dosage titration was used). The rate now appears to be 0.1% or less.

The evidence supporting lamotrigine usage for acute bipolar depression, however, is mixed. On the positive side, one double-blind, placebo-controlled study of lamotrigine (50 mg/d, 200 mg/d, or placebo) in bipolar I depression (n = 195) showed favorable results.¹ At 50 mg, 41% of patients improved;on 200 mg, 51% responded; and 26% improved on placebo.

These positive findings about lamotrigine had been countered, however, by four negative studies that are large, industry-supported, double-blind, placebo-controlled clinical trials studying lamotrigine treatment in acutely depressed bipolar I and II patients. None of the four studies found a statistical difference between lamotrigine and placebo. As a result, lamotrigine did not receive Food and Drug Administation approval for acute bipolar depression. A meta-analysis of these five studies, however found a small benefit with an overall effect size of 0.27.² In more severely ill patients (Hamilton 24 or more), lamotrigine had a greater separation from placebo (0.47) mostly because placebo effect was lower in this group. Lamotrigine was not better than placebo if the baseline Hamilton was lower than 24 (0.07 effect size). In another approach to predicting response, a small observational study showed better results at lamotrigine blood levels around 4 ng/mL.³

The efficacy of lamotrigine as maintenance therapy is fairly robust. Two large, 18-month studies showed efficacy, enabling lamotrigine to obtain FDA approval for maintenance use.^4,5 It had no efficacy for preventing mania, but at least it did not increase the risk of mania compared with placebo.

Lamotrigine has shown no efficacy in treating acute mania, which makes it less desirable than lithium, quetiapine, or cariprazine in that there will be no coverage for the manic/hypomanic phases. It also has no apparent benefit for suicidal ideation or behaviors. In fact, like all anticonvulsants, it carries a warning about possible increased risk of suicidality. On the other hand, its relatively benign side effect profile might make it a first choice for some patients, especially if the past hypomanias have been mild.

Lamotrigine might also be worth considering in women of childbearing potential. The teratogenic risk of lamotrigine is approximately 1% to 4%, the lowest among the antiepileptic medications. A large observational study found an odds ratio compared with controls of 1.3 for orofacial cleft abnormalities.⁶ If, after carefully weighing the options, lamotrigine is selected for these women, close monitoring of serum level is prudent as dosing and serum concentration dramatically differ depending on the stage of pregnancy.

Disclosures:

Dr Osser is Associate Professor of Psychiatry, Harvard Medical School, and Consulting Psychiatrist, US Department of Veterans Affairs, National Telemental Health Center, Bipolar Disorders Telehealth Program, Brockton, MA.

References:

1. Calabrese JR, Bowden CL, Sachs GS, et al, for the Lamictal 602 Study Group. Double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. J Clin Psychiatry. 1999;60:79-88.

2. Geddes JR, Burgess S, Hawton K, et al. Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. Am J Psychiatry. 2004;161:217-222.

3. Kesebir S, Akdeniz F, Demir A, Bilici M. A comparison before and after lamotrigine use in long-term continuation treatment: effect of blood level. J Mood Disord. 2013;3:47-51.

4. Bowden CL, Calabrese JR, Sachs G, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry. 2003;60:392-400.

5. Calabrese JR, Bowden CL, Sachs, G, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry. 2003;64:1013-1024.

6. Dolk H, Wang H, Loane M, et al. Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies. Neurology. 2016;86:1716-1725.