Lithium response and Val66Met polymorphism of the brain-derived neurotrophic factor gene in Japanese patients with bipolar disorder
Department of Psychiatry, Fujita Health University, Nagoya, Aichi, Japan Psychiatric Genetics
(Impact Factor: 1.94).
05/2006; 16(2):49-50. DOI: 10.1097/01.ypg.0000180680.72922.57
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.
Available from: Janusz Rybakowski
- "Furthermore, we have found a significant interaction of this polymorphism with that of the serotonin transporter where, in subjects with the s allele of 5-HTTLPR having a Val/Val genotype of BDNF, there is a 70 % probability of lithium non-response . However, an association of lithium response with a Val66Met polymorphism of the BDNF gene was not confirmed in populations other than Caucasian [38, 60]. "
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ABSTRACT: Mood stabilizers form a cornerstone in the long-term treatment of bipolar disorder. The first representative of their family was lithium, still considered a prototype drug for the prevention of manic and depressive recurrences in bipolar disorder. Along with carbamazepine and valproates, lithium belongs to the first generation of mood stabilizers, which appeared in psychiatric treatment in the 1960s. Atypical antipsychotics with mood-stabilizing properties and lamotrigine, which were introduced in the mid-1990s, form the second generation of such drugs. The response of patients with bipolar disorder to mood stabilizers has different levels of magnitude. About one-third of lithium-treated patients are excellent responders, showing total prevention of the episodes, and these patients are clinically characterized by an episodic clinical course, complete remission, a bipolar family history, low psychiatric co-morbidity and a hyperthymic temperament. It has been suggested that responders to carbamazepine or lamotrigine may differ clinically from responders to lithium. The main phenotype of the response to mood stabilizers is a degree of prevention against recurrences of manic and depressive episodes during long-term treatment. The most specific scale in this respect is the so-called Alda scale, where retrospective assessment of lithium response is scored on a 0-10 scale. The vast majority of data on genetic influences on the response to mood stabilizers has been gathered in relation to lithium. The studies on the mechanisms of action of lithium and on the neurobiology of bipolar disorder have led to the identification of a number of candidate genes. The genes studied for their association with lithium response have been those connected with neurotransmitters (serotonin, dopamine and glutamate), second messengers (phosphatidyl inositol [PI], cyclic adenosine-monophosphate [cAMP] and protein kinase C [PKC] pathways), substances involved in neuroprotection (brain-derived neurotrophic factor [BDNF] and glycogen synthase kinase 3-β [GSK-3β]) and a number of other miscellaneous genes. There are no published pharmacogenomic studies of mood stabilizers other than lithium, except for one study of the X-box binding protein 1 (XBP1) gene in relation to the efficacy of valproate. In recent years, a number of genome-wide association studies (GWAS) in bipolar disorders have been performed and some of those have also focused on lithium response. They suggest roles for the glutamatergic receptor AMPA (GRIA2) gene and the amiloride-sensitive cation channel 1 neuronal (ACCN1) gene in long-term lithium response. A promise for better elucidating the genetics of lithium response has been created by the formation of the Consortium on Lithium Genetics (ConLiGen) to establish the largest sample, to date, for the GWAS of lithium response in bipolar disorder. The sample currently comprises more than 1,200 patients, characterized by their response to lithium treatment according to the Alda scale. Preliminary results from this international study suggest a possible involvement of the sodium bicarbonate transporter (SLC4A10) gene in lithium response. It is concluded that the pharmacogenetics of response to mood stabilizers has recently become a growing field of research, especially so far as the pharmacogenetics of the response to lithium is concerned. Clearly, the ConLiGen project is a highly significant step in this research. Although the results of pharmacogenetic studies are of significant scientific value, their possible practical implications are yet to be seen.
Available from: Yiru Fang
- "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. "
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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.
Available from: Jurjen J Luykx
- "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). "
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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.
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