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Relationship Between UGT1A4 and UGT2B7 Polymorphisms and the Steady-State Plasma Concentrations of Lamotrigine in Patients With Treatment-Resistant Depressive Disorder Receiving Lamotrigine as Augmentation Therapy

Suzuki, Takeshi, PhD*; Mihara, Kazuo, MD, PhD; Nagai, Goyo, MD, PhD; Kagawa, Shoko, MD, PhD; Nakamura, Akifumi, MD, PhD; Nemoto, Kenji, MD, PhD; Kondo, Tsuyoshi, MD, PhD

doi: 10.1097/FTD.0000000000000577
Original Article

Background: In a previous study, the authors had shown that in treatment-resistant depressive disorder, an early therapeutic response to lamotrigine augmentation therapy is dependent on its plasma concentrations. Lamotrigine is mainly metabolized by UGT1A4 and UGT2B7, and polymorphisms of said UGTs that affect enzyme activities have been reported. This study investigated the effect of these polymorphisms on the steady-state plasma concentrations (Css) of lamotrigine in patients with treatment-resistant depressive disorder receiving lamotrigine as augmentation therapy.

Methods: The subjects were 103 depressed patients who had already shown insufficient response to at least 3 psychotropics including antidepressants, mood stabilizers, and atypical antipsychotics. The diagnoses were major depressive disorder (n = 46), bipolar II disorder (n = 44), and bipolar I disorder (n = 13). They received augmentation therapy with lamotrigine for 8 weeks. The final doses of lamotrigine were 100 mg/d for 67 subjects who were not taking valproate and 75 mg/d for 36 subjects taking valproate, respectively. Blood sampling was performed at the 8th week. Plasma concentrations of lamotrigine were measured by high-performance liquid chromatography. The genotypes of UGT1A4 142T>G, UGT2B7 -161C>T, and UGT2B7 372A>G were identified by polymerase chain reaction analyses.

Results: There were no significant relationships between these polymorphisms and the Css of lamotrigine in the subjects regardless of valproate comedication.

Conclusions: This study suggests that these genetic polymorphisms do not affect the Css of lamotrigine in patients with treatment-resistant depressive disorder receiving lamotrigine as augmentation therapy.

Departments of *Hospital Pharmacy and

Neuropsychiatry, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan.

Correspondence: Kazuo Mihara, MD, PhD, Department of Neuropsychiatry, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara-cho, Okinawa 903-0215, Japan (miharak@med.u-ryukyu.ac.jp).

Supported by Grant-in Aids from the Japanese Ministry of Education, Culture, Sports, Science, and Technology (#16790696, #19591366, #25461736, 17K10311, and 18K07607).

K. Mihara has received honoraria from GlaxoSmithKline and Otsuka. A. Nakamura has received honoraria from Dainippon Sumitomo Pharma and Otsuka. T. Kondo has received honoraria from Eli Lilly, GlaxoSmithKline, and Otsuka. The remaining authors declare no conflict of interest.

Received July 31, 2018

Accepted October 01, 2018

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.