A High Plasma Lamotrigine Concentration at Week 2 as a Risk Factor for Lamotrigine-Related Rash

Abstract

Background: Reportedly, a high plasma concentration of lamotrigine plays a role in the development of lamotrigine-related rash. The relationship between plasma concentrations of lamotrigine at week 2 and the lamotrigine-related rash was prospectively studied in 84 patients (22 males and 62 females) with treatment-resistant depressive disorder during an 8-week treatment of lamotrigine augmentation. Methods: Eighty-four depressed patients with an insufficient response to at least 3 psychotropics, including antidepressants, mood stabilizers, and atypical antipsychotics, were included. The diagnoses were major depressive disorder (n = 39), bipolar I disorder (n = 10), and bipolar II disorder (n = 35). The final doses of lamotrigine were 100 mg/d for 57 subjects who were not taking valproate and 75 mg/d for 27 subjects taking valproate. Blood sampling was performed at week 2. Lamotrigine plasma concentrations were measured using high-performance liquid chromatography. The development of lamotrigine-related rash was assessed during the 8-week treatment. Results: Six females developed lamotrigine-related rash. The mean plasma lamotrigine concentrations at week 2 were significantly (P = 0.009) higher in the rash group (4.81 ± 1.23 μmol/L) than in the nonrash group (3.35 ± 1.39 μmol/L). Receiver-operating characteristic analysis indicated that a plasma lamotrigine concentration of 4.38 μmol/L or greater at week 2 was significantly (P < 0.0001) predictive of lamotrigine-related rash. The proportion of patients with a lamotrigine concentration of 4.38 μmol/L or greater was significantly divided by the cutoff point into the rash group and the nonrash group (5/1 versus 13/65, P = 0.001). Conclusions: This study suggests that a high plasma lamotrigine concentration during week 2 is a risk factor for lamotrigine-related rash and a plasma lamotrigine concentration of 4.38 μmol/L may be a considered a threshold for rash in treatment-resistant depressive disorder.

Impact of Selected Initial Titration Schedules on Safety and Long-Term Effectiveness of Lamotrigine for the Treatment of Mood Disorders

“…Previous studies have reported that very slow titration schedules prevented the recurrence of rashes during rechallenge after the first occurrence of a LTG-induced rash 15 and that low plasma LTG concentration 2 weeks after initiation was associated with a low risk of rash. 16 The results of this study are consistent with those of previous studies regarding the risk of LTG-induced rash development in patients with epilepsy. Concomitant use of VPA 3,5,11 and female sex 5,17 have been reported to increase the risk of developing LTG-induced rashes.…”

“…Although the small sample size in the fast titration group might have affected accurate estimation, fast titration significantly increased the risk of rash development and slow titration significantly decreased this risk, suggesting that slow titration during the initiation of LTG reduces the risk of rash development in patients with mood disorders. Previous studies have reported that very slow titration schedules prevented the recurrence of rashes during rechallenge after the first occurrence of a LTG-induced rash 15 and that low plasma LTG concentration 2 weeks after initiation was associated with a low risk of rash 16 …”

Association of Optimal Lamotrigine Serum Levels and Therapeutic Efficacy in Mood Disorders

“…Skin rash is the prevalent adverse reaction of LAM that mostly results in the withdrawal of LAM. A recent study showed a high mean plasma concentration (4.38 ± 1.23 μmol/L) at week 2 as a risk factor for LAM-related rash 28 . Usual risk factors for developing a LAM-related rash are: rapid titration, high LAM starting dose, history of rash after another antiepileptic drug, and simultaneous valproate treatment.…”

“…A recent study showed a high mean plasma concentration (4.38 ± 1.23 μmol/L) at week 2 as a risk factor for LAM-related rash. 28 Usual risk factors for developing a LAM-related rash are: rapid titration, high LAM starting dose, history of rash after another antiepileptic drug, and simultaneous valproate treatment. In addition, the frequency of severe rashes with LAM such as Steven-Johnson syndrome and toxic epidermal necrolysis had a dramatic decline with the initiation of a step-bystep titration schedule in 1994.…”