Predicting factors for valproate treatment outcome among bipolar II patients – focused on GNB3 and CRP level

Abstract

Background: Valproate (VPA) is a mood stabilizer for the treatment of bipolar II disorder (BD II) patients but it may cause metabolic disturbances in certain patients Genetic and environmental factors may involve in individual difference of metabolic disturbances Genetic factors include PPAR-γ gene leptin receptor gene (LEPR) guanosine nucleotide-binding proteins (G protein) associated gene etc Guanine nucleotide-binding protein beta 3 (GNB3) gene encodes the β3 subunit of heterotrimeric G proteins which is the key component of intracellular signal transduction of metabolic regulation In addition increased level of C-reactive protein (CRP) a sensitive marker of inflammation was associated with disease progress of BD and the association between plasma CRP level and metabolic indices had been found in previous study Add-on memantine a kind of anti-inflammation drug may improve metabolic disturbances in BD patients However there were no studies focusing on GNB3 polymorphism and CRP level as predicting factors for VPA treatment outcome among BD II patients Materials and Methods: Patients (aged 18–65 years) who met the DSM-IV and the Chinese Version of SADS-L diagnostic criteria for BD II were enrolled consecutively by trained psychiatrists In addition baseline HDRS score of all patients were > 18 which considered as bipolar depression state All patients were randomized to VPA + placebo or VPA + memantine group We also collected fasting blood samples between 8–10 am to measure metabolic indices CRP level and the genotype of GNB3 C825T (rs5443) In addition body mass index (BMI) waist circumference disease severity and cognitive function were also measured Results: We recruited 211 bipolar II disorder patients among of whom 95 patients dropped out during the study period The mean age of recruited patients was 31 89 ± 11 44 years and a total of 54 5% of the patients was female Result 1: At baseline BD II patients with CC genotype of GNB3 C825T polymorphism had the highest triglyceride (TG) level During the treatment period body mass index (BMI) cholesterol TG low density lipoprotein (LDL) and leptin level were significantly associated with this polymorphism In addition after 12-week treatment cognitive function in the CT and CC groups were significantly improved Result 2: At baseline no significant difference were found between VPA + placebo and VPA + memantine groups no matter the baseline CRP level We sub-grouped our patients based on baseline level of CRP at 2322 ng/mL In CRP level >2322 ng/mL group there were significant differences in BMI waist circumference cholesterol LDL LDL/HDL ratio and CRP between VPA + placebo and VPA + memantine groups during the treatment period However cognitive function was not significantly improved after 12-week treatment in two groups In CRP level ?2322 ng/mL group there were significant differences in HDRS score and TG between two groups during the treatment period In addition cognitive function in the VPA + placebo group was significantly improved after 12-week treatment Result 3: The basal level of BMI waist circumference TG AC glucose insulin homeostasis model assessment-insulin resistance (HOMA-IR) homeostasis model assessment-insulin resistance-β cell function (HOMA-β) leptin and CRP level were significantly different among TT+CT & CRP?2322 ng/mL group TT+CT & CRP>2322 ng/mL group CC & CRP?2322 ng/mL group and CC & CRP>2322 ng/mL group During the treatment period there were significant differences in insulin and HOMA-IR among four groups Conclusions: This study indicated that BD II patients with CC genotype of GNB3 C825T and the baseline level of CRP>2322 ng/mL have worse VPA-induced metabolic disturbances Both the genotype of GNB3 C825T and the level of CRP could be biomarkers to predict VPA treatment outcome In the future study we may use complicated models such as functional linear model or artificial neural networks to predict VPA treatment outcome

Date of Award	2015 Jul 6
Original language	English
Supervisor	Hui-Hua Chang (Supervisor)