Prophylactic Lithium Response and Polymorphism of the Brain-Derived Neurotrophic Factor Gene

Introduction: Brain-derived neurotrophic factor (BDNF) has been involved in the pathogenesis of bipolar mood disorder and in the mechanism of mood-normalizing action of lithium. The aim of this study was to find a possible association between lithium prophylactic effect in bipolar patients and two polymorphisms of BDNF gene. Methods: Eighty-eight patients (35 males, 53 females) with bipolar illness were studied. Duration of lithium prophylaxis ranged between 5-27 years (mean 15 years). Three categories of prophylactic lithium response were delineated: excellent responders (ER), partial responders (PR) and non-responders (NR). All patients were genotyped for two polymorphisms of BDNF gene: Val66Met and -270C/T. Results: The Val/Met genotype of Val66Met polymorphism occurred more frequently (p = 0.037) and there was a trend for a higher incidence of Met allele (p = 0.076), in ER than in NR. A trend for C/T genotype and T allele of -270C/T polymorphism was observed to occur more frequently in ER than in NR (p = 0.057 and p = 0.065, respectively). Conclusion: The data obtained suggest that polymorphism of BDNF gene may be connected with a quality of lithium prophylaxis.

References

• 1 Angelucci F, Aloe L, Jiménez-Vasquez P, Mathé A A. Lithium treatment alters brain concentrations of nerve growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in rat model of depression.  Int J Neuropsychopharmacol. 2003;  6 225-231
• 2 Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N. et al . Characterization of single-nucleotide polymorphisms in coding regions of human genes.  Nat Genet. 1999;  22 231-238
• 3 Egan M, Kojima M, Callicot J H, Goldberg T E, Kolachana B S, Bertolino A. et al . The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function.  Cell. 2003;  112 257-269
• 4 Fukumoto T, Morinobu S, Okamoto Y, Kahaya A, Yamawaki S. Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain.  Psychopharmacology. 2001;  158 100-106
• 5 Geller B, Badner J A, Tillman R, Christian S L, Bolhofner K, Cook EH J r. Linkage disequilibrium of the brain-derived neurotrophic factor Val66Met polymorphism in children with a prepubertal and early adolescent bipolar disorder phenotype.  Am J Psychiatry. 2004;  161 1698-1700
• 6 Hashimoto R, Takei N, Shimazu K, Christ L, Lu B, Chuang D M. Lithium induces brain-derived neurotrophic factor and activities TrkB in rodent cortical neurons: an essential step for neuroprotection against glutamate neurotoxicity.  Neuropharmacology. 2002;  43 1173-1179
• 7 Hashimoto K, Shimizu E, Iyo M. Critical role of brain-derived neurotrophic factor in mood disorders.  Brain Res Brain Res Rev. 2004;  45 104-114
• 8 Holoubek G, Noldner M, Treiber K, Muller W E. Effect of chronic antidepressant treatment on beta-receptor coupled signal transduction cascade.  Which effect matters most? Pharmacopsychiatry. 2004;  37 (Suppl 2) S113-119
• 9 Hong C J, Huo S J, Yen F C, Tung C L, Pan G M, Tsai S J. Association study of a brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal behavior.  Neuropsychobiology. 2003;  48 86-189
• 10 Jacobsen J P, Mork A. The effect of escitalopram, desipramine, electroconvulsive seizures and lithium on brain-derived neurotrophic factor mRNA and protein expression in the rat brain and the correlation to 5-HT and 5-HIAA levels.  Brain Res. 2004;  1024 183-192
• 11 Kunugi H, Ueki M, Otsuga M, Isse K, Hirasawa H, Kato N. et al . A novel polymorphism of the brain-derived neurotrophic factor (BDNF) gene associated with late-onset Alzheimer’s disease.  Mol Psychiatry. 2001;  6 83-86
• 12 Kunugi H, Iijima Y, Tatsumi M, Yoshida M, Hashimoto R, Kato T. et al . No association between the Val66Met polymorphism of the brain-derived neurotrophic factor gene and bipolar disorder in a Japanese population: a multicenter study.  Biol Psychiatry. 2004;  56 376-378
• 13 Lu B. BDNF and activity-dependent synaptic modulation.  Learn Mem. 2003;  10 86-98
• 14 Manji H K, Zarate C A. Molecular and cellular mechanism underlying mood stabilization in bipolar disorder: implications for the development of improved therapeutics.  Mol Psychiatry. 2002;  7 S1-S7
• 15 Miller S A, Dykaes D D, Polesky H F. A simple salting out procedure for extracting DNA from human nucleated cells.  Nucleic Acid Res. 1988;  16 1215
• 16 Nakata K, Ujike H, Sakai A, Uchida N, Nomura A, Imamura T. et al . Association study of the brain-derived neurotrophic factor (BDNF) gene with bipolar disorder.  Neurosci Lett. 2003;  337 17-20
• 17 Neves-Pereira M, Mundo E, Muglia P, King N, Macciardi F, Kennedy J L. The brain-derived neurotropic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study.  Am J Hum Genet. 2002;  71 651-655
• 18 Oswald P, Del-Favero J, Massat I, Souery D, Claes S, Van Broeckhoven C. et al . Non-replication of the brain-derived neurotrophic factor (BDNF) association in bipolar affective disorder: a Belgian patient-control study.  Am J Med Genet. 2004;  129B 34-35
• 19 Proschel  M, Saunders A, Roses A D, Muller C R. Dinucleotide repeat polymorphism at the human gene for the brain-derived neurotrophic factor (BDNF).  Hum Mol Genet. 1992;  1 353
• 20 Rowe M K, Chuang D M. Lithium neuroprotection: molecular mechanisms and clinical implications.  Expert Rev Mol Med. 2004;  6 1-18
• 21 Rybakowski J K, Borkowska A, Czerski P M, Skibińska M, Hauser J. Polymorphism of the brain-derived neurotrophic factor gene and performance on a cognitive prefrontal test in bipolar patients.  Bipolar Disord. 2003;  5 468-472
• 22 Rybakowski J K, Suwalska A, Czerski P M, Dmitrzak-Weglarz M, Leszczyńska-Rodziewicz A, Hauser J. Prophylactic effect of lithium in bipolar affective illness may be related to serotonin transporter genotype. Pol J Pharmacol 2004: (in press)
• 23 Serretti A, Lilli R, Mandelli L, Lorenzi C, Smeraldi E. Serotonin transporter gene associated with lithium prophylaxis in mood disorders.  Pharmacogenomics J. 2001;  1 71-77
• 24 Siuciak J A, Lewis D R, Wiegand S J, Lindsay R M. Antidepressant-like effect of brain-derived neurotrophic factor (BDNF).  Pharmacol Biochem Behav. 1997;  56 131-137
• 25 Skibińska M, Hauser J, Czerski P M, Leszczyńska-Rodziewicz A, Kosmowska M, Kapelski P. et al . Association analysis of brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism in schizophrenia and bipolar affective disorder.  World J Biol Psychiatry. 2004;  5 215-220
• 26 Sklar P, Gabriel S B, McInnis M G, Bennet P, Lim Y M, Tsan G. et al . Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus.  Mol Psychiatry. 2002;  7 579-593
• 27 Strauss J, Barr C L, George C J, King N, Shaikh S, Devlin B. et al . Association study of brain-derived neurotrophic factor in adults with a history of childhood onset mood disorder.  Am J Med Genet.. 2004;  131B 16-19
• 28 Szczepankiewicz A, Skibinska M, Czerski P M, Kapelski P, Leszczynska-Rodziewicz A, Slopien A. et al .No association of the Brain-Derived Neurotrophic Factor (BDNF) gene C-270T polymorphism with schizophrenia. Schizophr Res 2005: (in press)
• 29 Tsai S -J, Hong C -J, Yu Y W-Y, Chen T -J. Association study of a brain-derived neurotrophic factor (BDNF) Val66met polymorphism and personality trait and intelligence in healthy young females.  Neuropsychobiol. 2004;  49 13-16
• 30 Turecki G, Grof P, Grof E, D’Souza V, Lebuis L, Marineau C. et al . Mapping susceptibility genes for bipolar disorder: a pharmacogenetic approach based on excellent response to lithium.  Mol Psychiatry. 2001;  6 570-578
• 31 Tyler W J, Alonso M, Bramham C R, Pozzo-Miller L D. From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning.  Learn Mem. 2002;  9 224-237
• 32 Yamada K, Mizuno M, Nabeshima T. Role for brain-derived neurotrophic factor in learning and memory.  Life Sci. 2002;  70 735-744