Lithium response and Val66Met polymorphism of the brain-derived neurotrophic factor gene in Japanese patients with bipolar disorder
ABSTRACT Lithium is a first-line agent for the treatment of bipolar disorder. A significant association between the Val66Met polymorphism of the brain-derived neurotrophic factor gene and bipolar disorder has been reported. We investigated whether this polymorphism is associated with the response to lithium treatment in Japanese patients with bipolar disorder. Patients had been treated with lithium carbonate for more than 1 year, and the response was retrospectively evaluated. No significant differences were found in the genotype distribution or allele frequency between responders and non-responders. Our results suggested that the brain-derived neurotrophic factor Val66Met polymorphism might not greatly contribute to the efficacy of lithium in bipolar disorder.
- SourceAvailable from: Yiru Fang
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- "Recently, a cohort study of multiplex bipolar families added to the body of evidence associating Val66Met polymorphism with BPD (Sears et al. 2011). Similarly, an association of Val66Met polymorphism with a degree of prophylactic lithium response was found in a Poland population (Dmitrzak-Weglarz et al. 2008; Rybakowski et al. 2005, 2007), which was not replicated in Japanese patients with BPD (Masui et al. 2006). Therefore, the aim of the present study is to investigate potential association between BDNF gene Val66Met functional polymorphism (rs6265) and susceptibility to BPD, treatment response to mood stabilizers in patients with BPD in a Han Chinese population. "
ABSTRACT: Recent data suggest that brain-derived neurotrophic factor (BDNF) plays an essential role in neuronal plasticity and etiology of bipolar disorders (BPD). However, results from different studies have been inconsistent. In present study, 342 patients who met DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition) criteria for bipolar disorders type I (BPD-I) or type II (BPD-II) and 386 matched health controls were enrolled, and TaqMan(®) SNP Genotyping Assays (Applied Biosystems, Foster City, CA, USA) were applied to detect the functional polymorphism rs6265 (Val66Met) of BDNF gene. Treatment response to lithium and valproate was retrospectively determined. The association between Val66Met polymorphism and BPD, treatment response to mood stabilizers, was estimated. The genotype and allele distribution of Val66Met polymorphism between BPD patients and control subjects showed significant difference (genotype: χ(2) = 6.18, df = 2, P = 0.046; allele: χ(2) = 5.01, df = 1, P = 0.025) with Met allele as risk factor for disease susceptibility (OR = 0.79, 95%CI as 0.64-0.97). The post hoc analysis interestingly showed that Met allele had opposite effect on the treatment response for BPD-I and BPD-II separately. For BPD-I patients, the response score in Val/Val group was significantly lower than that in Met allele carriers (t = -2.27, df = 144, P = 0.025); for BPD-II patients, the response score in Val/Val group was significantly higher than that in Met allele carriers (t = 2.33, df = 26, P = 0.028). Although these results should be interpreted with caution because of the limited sample for Val/Val genotype in BPD-II patients (N = 5), these findings strengthen the hypothesis that BDNF pathway gets involved in the etiology and pharmacology of BPD and suggest the differences between BPD-I and BPD-II.Genes Brain and Behavior 04/2012; 11(5):524-8. DOI:10.1111/j.1601-183X.2012.00797.x
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- "Some investigators performed genome-wide scans with microsatellites and found evidence for genetic effects of Li response on 12q23-q24 and 7q11.2 (Morissette et al., 1999; Mamdani et al., 2004). Preliminary evidence that single gene polymorphisms influence Li response in BD exists for BDNF, BCR, CREB, CACNG2, 5-HTTLPR and GSK3β (Mamdani et al., 2004, 2008; Rybakowski et al., 2005, 2007; Masui et al., 2006, 2008; Serretti et al., 2001; Silberberg et al., 2008; Benedetti et al., 2005). Administration of Li and carbamazepine increased membrane GRK3 protein in the frontal cortex of rats (Ertley et al., 2007). "
ABSTRACT: We aimed to get a comprehensive insight into the genetic evidence supporting the role of GSK3beta in bipolar disorder (BD). Using broad searches in NCBI's PubMed and the Genetic Association Database we looked for association, whole-genome linkage, genome-wide association, gene expression, pharmocogenomic, epigenetic, cytogenetic, and mouse model studies performed for BD until July 2009. Per gene, we rated the degree of converging evidence across these types of genetic studies. The genes most consistently associated with BD in the genetic studies we reviewed were GSK3beta , GRK3, 5-HTTLPR, GRIN3, COMT, and GLUR3. GSK3beta stood out as it was implicated in at least five types of genetic studies. Although our results are limited by design differences of included studies and possibly by publication bias, GSK3beta is a plausible candidate gene for BD from a pharmacological and a genetic perspective. Future studies investigating the effects of GSK3beta manipulation in BD seem warranted.European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 03/2010; 20(6):357-68. DOI:10.1016/j.euroneuro.2010.02.008
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- "There is evidence of an involvement of BDNF in lithium prophylactic efficacy. Rybakowski et al. (2005) reported an association between the rs6265 A-allele and a better response to lithium prophylactic treatment for BP disorder, though no replication could be obtained on a Asiatic sample (Masui et al., 2006). Further, Rybakowski et al. found BDNF significantly interacting with SERT gene (5-HTTLPR polymorphism) in moderating the efficacy of lithium treatment (Rybakowski et al., 2007b). "
ABSTRACT: Brain-derived neurotrophic factor is a candidate gene for response to antidepressant treatment. However, response to pharmacological treatments is moderated by both genetic and other factors within individuals. For example, there is evidence of an influence of the temperamental trait of harm avoidance on the outcome of depressive disorders. In the present study we aimed to investigate the effect of the brain-derived neurotrophic factor gene on medium-term outcome in a naturalistic sample of 86 depressed bipolar spectrum patients, taking into account harm avoidance. Both single marker and haplotypes were significantly associated with severity of depression at month 6 after treatment initiation. The haplotype comprising the A-C alleles was associated with a poorer outcome. Harm avoidance maintained a significant effect on depressive outcome in bipolar disorder, independently from brain-derived neurotrophic factor genotypes. However, harm avoidance s influence appeared to be more consistent in patients carrying the protective G-T combination of alleles. Our results indicate brain-derived neurotrophic factor as involved in the outcome of depression in bipolar disorder. Harm avoidance did not interact with brain-derived neurotrophic factor genotypes, though its effect was still significant. Given that many factors may influence response to pharmacological treatments, studies that consider personality and other individual characteristics are warranted also in pharmacogenetic investigations.Journal of Psychopharmacology 02/2010; 24(12):1747-54. DOI:10.1177/0269881109353463