How to Maximize Lamotrigine’s Efficacy

Lamotrigine has an undeserved reputation as a “weak” mood stabilizer. That skepticism has its origins in a series of 5 randomized controlled trials (RCTs) from the 1990s that barely detected an effect in bipolar depression (only 1 in 11 patients improved). After that setback, lamotrigine went on to receive FDA approval in 2003 for the prevention of new episodes in bipolar disorder, based on robust data from 2 large RCTs lasting 1.5 years each.[1]

Preventative efficacy is not an afterthought for a failed drug. Rather, it is the primary endpoint for chronic disorders like bipolar. The trouble is that preventative benefits are more difficult to discern than acute ones. Before giving up on lamotrigine, compare the frequency of episodes in the years before and after starting the drug. A 50% reduction is a good response.

Most outcome studies focus on full episodes, but subsyndromal mood swings are a common and disruptive force in the lives of patients with bipolar disorder. These daily mood problems were reduced 1.8-fold by lamotrigine in an analysis of mood charts from a 6-month RCT.[3]

Daily mood swings (called ultradian cycling) take a toll on work and relationships, and the chaotic stressors that emerge from them can sometimes distract from the underlying lability that often causes such stressors. This type of cycling is common in cyclothymic and borderline personality disorders, the subject of our next slides.

Although cyclothymia is common in clinical practice, there are no controlled pharmacotherapy trials in this population. In my experience, it is these patients who have the best results with lamotrigine. Anecdotal reports support that observation,[4] as does the research on daily mood fluctuations in the last slide.[3]

Controlled trials do support lamotrigine’s role in borderline personality disorder (BPD), and a Cochrane review concluded that the evidence for lamotrigine in BPD was more robust than it was for antidepressants.[5] BPD and cyclothymia are both common in bipolar II patients (around 40%),[6,7] and there is speculation that cyclothymia represents the temperamental underpinnings of BPD.[6] There is at least symptomatic overlap between the 2 disorders: lability, irritability, rejection sensitivity, and impulsivity are prominent in both.

In addition to BPD, small controlled trials suggest lamotrigine improves cognition and reduces anxiety and cocaine use in bipolar patients (the later effect is mild).[8-10] Controlled trials also support its use in obsessive-compulsive disorder, depersonalization disorder, PTSD, treatment-resistant schizophrenia, and obesity.[11,12]

Well-designed studies in unipolar depression and acute mania have not been successful, although lamotrigine does prevent manic and mixed episodes and has no known risk of triggering mania.[1]

Though the optimal dose needs to be personalized, research suggests that 150 mg/d to 250 mg/d works best for most patients. In a dose-comparison study, 200 mg outperformed lower (50 mg) and higher (400 mg) doses of the drug.[13] Flexible dose studies tended to arrive at a daily dose of 150 mg when the protocol allowed a maximum of 200 mg, or 250 mg if the maximum was 400 mg.[1]

Several interactions require adjustments to that dose, most commonly:

• Valproate: Doubles lamotrigine levels.[1]

• Carbamazepine: Lowers lamotrigine levels by 50%.[1]

• Contraceptives with ethinyl estradiol: Lower lamotrigine levels by 40% to 60% (there is no interaction with non-hormonal IUDs or levonorgestrel-releasing IUDs).[14]

Although serum lamotrigine levels are generally not recommended,[15] they can be useful in patients with unusual reactions to the drug, UGT1A4 polymorphisms (which can alter lamotrigine levels), or pregnancy (lamotrigine levels drop significantly after the first trimester).[16]

Although folic acid can augment antidepressants and valproate, this supplement actually prevented lamotrigine from working in a recent RCT.[2] The mechanism behind this interaction is not clear, but it is not known to occur with folate, folinic acid, or L-methylfolate (folic acid is the synthetic form of the vitamin, and problems in its metabolism have been linked to various health risks).[17]

Identifying the right patients for lamotrigine is the best way to maximize its benefits. Next month, we’ll review ways to minimize the medication’s adverse effects, including the severe skin reactions that are its most serious risk.