Genome-Wide Association Study of Lithium-Induced Dry Mouth in Bipolar I Disorder

Lawrence Shih-Hsin Wu,Chun-Yuan Lin,Chih-Ken Chen,Cathy Shen-Jang Fann,Andrew Tai-Ann Cheng,Chih-Chien Lin,Chen-Yang Shen,Ming-Chyi Huang

doi:10.3390/jpm11121265

Abstract

Dry mouth is a rather common unpleasant adverse drug reaction (ADR) to lithium treatment in bipolar disorders that often lead to poor adherence or early dropout. The aim of this study was to identify the genetic variants of dry mouth associated with lithium treatment in patients with bipolar I (BPI) disorder. In total, 1242 BPI patients who had ever received lithium treatment were identified by the Taiwan Bipolar Consortium for this study. The proportions of patients who experienced impaired drug compliance during lithium medication were comparable between those only with dry mouth and those with any other ADR (86% and 93%, respectively). Dry mouth appeared to be the most prevalent (47.3%) ADR induced by lithium treatment. From the study patients, 921 were included in a genome-wide association study (GWAS), and replication was conducted in the remaining 321 patients. The SNP rs10135918, located in the immunoglobulin heavy chain locus (IGH), showed the strongest associations in the GWAS (p = 2.12 × 10−37) and replication groups (p = 6.36 × 10−13) (dominant model) for dry mouth with a sensitivity of 84.9% in predicting dry mouth induced by lithium. Our results may be translated into clinical recommendation to help identify at-risk individuals for early identification and management of dry mouth, which will improve medication adherence.

Highlights

Bipolar I (BPI) disorder is a severe, chronic, and disabling mental illness characterized by pathological mood swings with a high tendency to recur [1,2]
Among 1242 bipolar I (BPI) patients receiving maintenance treatment of lithium, the most common adverse drug reaction (ADR) was found to be dry mouth, which was associated with markedly impaired drug adherence with or without combination medication of other psychotropics
To the best of our knowledge, this is the first study to identify a significant genetic variant for dry mouth induced by lithium maintenance treatment

Summary

Introduction

Bipolar I (BPI) disorder is a severe, chronic, and disabling mental illness characterized by pathological mood swings with a high tendency to recur [1,2]. Lithium has been placed as a treatment of choice, for acute mania and the augmentation of antidepressant in unipolar depression [3], and for the long-term prevention of manic and depressive recurrences [2,4]. The prophylactic benefits from lithium treatment are hindered primarily by its long-term effects on major organ systems, especially the kidneys [5], as well as poor drug adherence [6,7]. Research has shown that non-adherence to lithium is very common, with an average rate of 44.7% (ranging from 18% to 52%) [8,9,10]. One of the commonly reported reasons for the non-adherence to lithium medication is the presence of adverse drug reactions (ADRs) [6,9]. In a five-year prospective study among 402 BPI patients receiving lithium maintenance treatment, 28% of them attributed their premature discontinuation of lithium to ADRs [11]

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