Psychiatry Research 180 (2010) 54–56
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The role of genetic variation of BDNF gene in antidepressant-induced mania in bipolar disorder Alexandre de Aguiar Ferreira a, Fernando Silva Neves b, Guilherme José Garcia Santos Pimenta c, Marina Pena Mello c, Débora Marques Miranda c, Marco Aurélio Romano-Silva a,c, Luiz Armando De Marco d, Humberto Corrêa a,b,c,⁎ a
Neuroscience Program, Institute of Biological Sciences, Federal University of Minas Gerais (ICB-UFMG), Belo Horizonte, Brazil Cellular Biology Program, Institute of Biological Sciences, Federal University of Minas Gerais (ICB-UFMG), Belo Horizonte, Brazil c Laboratory of Neuroscience, Department of Mental Health, Faculty of Medicine, Federal University of Minas Gerais (FM-UFMG), Belo Horizonte, Brazil d Pharmacology Department, Institute of Biological Sciences, Federal University of Minas Gerais (ICB-UFMG), Belo Horizonte, Brazil b
a r t i c l e
i n f o
Article history: Received 18 November 2008 Received in revised form 8 March 2010 Accepted 21 April 2010 Keywords: Brain-derived neurotrophic factor (BDNF) gene Antidepressant-induced mania Bipolar disorder
a b s t r a c t The occurrence of mania during antidepressant treatment is a key issue in the clinical management of bipolar disorder (BD). Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of mood disorders. Moreover, antidepressants increase the expression of BDNF and its overactivity may be involved in the mechanism of development of the manic state. The aim of the present study was to test the inﬂuence of BDNF gene alterations in antidepressant-induced mania in bipolar patients. A case–control study was performed to analyse genotype and allele frequencies for the BDNF polymorphisms between two groups [37 patients with antidepressant-induced mania (AIM+) and 55 patients without antidepressant-induced mania (AIM−)]. No signiﬁcant differences were found between AIM+ and AIM− groups. Our results did not support the BDNF gene link to antidepressant-induced mania, like a previous study with a smaller sample has already suggested. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, regulates many aspects of neural function. In the mature nervous system, neurotrophic factors control synaptic plasticity, while continuing to modulate neuronal survival and neuronal signal transduction across multiple neurotransmitter systems (Huang and Reichardt, 2001). Several studies suggest that BDNF plays a role in the pathogenesis of major depression and is also involved in antidepressant action, based on observations that reduction in hippocampal BDNF levels is correlated with depressive symptoms and that antidepressant treatment enhances the expression of BDNF (Smith et al., 1995; Duman et al., 1997; Duman and Monteggia, 1997; Duman, 1998; Angelucci et al., 2000; Hashimoto et al. 2004; Gonul et al., 2005; Martinowich et al., 2007; Schmidt and Duman, 2007; Kozisek et al., 2008). Indeed, aberrant regulation of neuronal plasticity, including neurogenesis mediated by neurotrophic factors in the hippocampus and other limbic nuclei results in maladaptive changes in neural networks, possibly underlying the ⁎ Corresponding author. Department of Mental Health, Faculty of Medicine, Federal University of Minas Gerais, Alfredo Balena Avenue, 190, CEP 30130-100, Belo Horizonte-MG, Brazil. Tel.: +55 031 3248 9785. E-mail address: [email protected]
(H. Corrêa). 0165-1781/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2010.04.036
pathophysiology of major depression (Schmidt and Duman, 2007). Furthermore, a recent study showed that antidepressant treatment raises activity-dependent neuronal plasticity by activation of BDNF, thereby gradually restoring network function and ultimately mood (Kozisek et al., 2008). Additional data strengthen the role of BDNF in affective disorders such as the BDNF overactivity present in manic state (Tsai, 2004), the association between BDNF polymorphisms and BD (bipolar disorder) (Neves-Pereira et al., 2002; Sklar et al., 2002; Hashimoto et al., 2004) and the fact that mood stabilizers modulate the activity of a BDNF promoter (Yasuda et al., 2009). Moreover, it has been shown that antidepressant-induced mania (AIM) appears to increase the risk of a long-term rapid-cycling course in bipolar patients (Ghaemi et al., 2000) and the Val66Met polymorphism of BDNF is associated with susceptibility to the rapid-cycling subset of the BD (Green et al., 2006; Müller et al., 2006). Taken together, these data provide a biological rationale suggesting that variations of BDNF expression or function, due to genetic polymorphisms, might contribute to the pathogenesis of antidepressant-induced mania, a crucial issue in the clinical management of the BD. Nevertheless, a recent study did not ﬁnd an association between some BDNF polymorphisms and antidepressant-induced mania (Zai et al., 2007). To our knowledge, however, it is the only study that has speciﬁcally addressed this question and more research is necessary to better clarify this point.
A.A. Ferreira et al. / Psychiatry Research 180 (2010) 54–56
Therefore, in this report we investigated the role of BDNF polymorphisms in mania/hypomania antidepressant induction in bipolardisordered patients. 2. Methods In our study 92 patients, all of them from the Bipolar Treatment Unit of the IPSEMG (Instituto de Previdência dos Servidores do Estado de Minas Gerais), an outpatient setting, were selected after a careful review of 280 patients (bipolar I and II) to assess for antidepressant-induced mania history. Diagnosis was made by a trained psychiatrist using a structured interview, MINI-PLUS, following DSM-IV criteria (Amorim, 2000) as well as a complete review of medical records and an interview with at least a close relative member. The local ethics committee approved the study and written informed consent was obtained from each participant. The patients were divided into two groups as follows: The ﬁrst group, named Antidepressive-Induced Mania (AIM+), consisted of 37 patients with a history of at least one depressive phase of the disorder who presented a manic or hypomanic episode within the ﬁrst sixty days of using a proserotonergic antidepressant drug regimen. Sixty days (about eight weeks) is the period of time that we have to expect an antidepressant response (American Psychiatric Association, 2000). The second group, named AIM−, consisted of 55 patients with a history of at least one depressive phase who, after treatment with proserotonergic antidepressant did not present with a manic or hypomanic episode within the ﬁrst sixty days of antidepressant treatment. In the AIM+ group, 41% (n = 15) of the patients were without a mood stabilizer in mania episode appearance. In the AIM− group, 36% (n = 20) of the patients were in the same condition. There was no statistical signiﬁcance for this difference between the groups. These patients that were without a mood stabilizer at the time of our evaluation had a previous unipolar depression misdiagnosis. The proserotonergic antidepressants evaluated in this study were SSRI, tricyclics and venlafaxine and were grouped together because all of them block serotonin reuptake transporters. In our study, about 15% of the patients have comorbidity with substance-related disorders. There are no statistical differences in the distribution of these comorbidities in the AIM+ and AIM− groups. Gender, age, diagnostic subtype variables, comorbidity with substance-related disorders and absence of mood stabilizer between groups are shown in Table 1. Blood sample was collected and DNA obtained by a high salt method. Genotyping was performed using Taqman genotyping assay made-to-order [rs4923463 (A/G polymorphism), rs6265 (G/A Val66Met polymorphism), rs2049045 (G/C polymorphism) and rs7103411 (T/C polymorphism)] (Applied Biosystems, Foster City, CA). These tagSNPs were selected based on the Hapmap Project (Hapmap Caucasian), and the BDNF gene is highly conserved being necessary only the tagSNPs chosen to cover the whole gene. All genotypes were performed in an Mx3005P QPCR System (Stratagene, Cedar Creek, TX) in an allelic discrimination mode. Haplotype analyses were performed using Unfased Software version 3.0.12. Linkage disequilibrium (LD) across the SNPs was performed using the Haploview program (version 2.03) to determine haplotype blocks. The level of signiﬁcance was set at 0.05, and results are shown in Table 2. Comparison of genotype and allele frequencies between groups was performed using the chi-square test. The level of signiﬁcance was set as P b 0.05. Our statistical power for this study is 66.2% considering the incidence of 30% of antidepressantinduced mania for bipolar patients (Goldberg and Truman, 2003). The “Statistical Power Calculator” in DSS Research Program was used for the power analysis.
3. Results The two groups were evaluated according to gender, age and diagnostic subtype of bipolar disorder and no signiﬁcant differences were found between both groups. There were no signiﬁcant deviations from the Hardy–Weinberg equilibrium of the BDNF genotype sample distribution.
Table 1 Gender, age, diagnostic subtype variables, comorbidity with substance-related disorders and absence of mood stabilizer between groups (AIM+ vs. AIM−).
Gender, M/F Age (mean ± S.D.) BD subtype I, No. (%) BD subtype II, No. (%) BD NOS, No. (%) Substance-related disorders Absence of mood stabilizer
Group AIM+ (n = 37)
Group AIM− (n = 55)
08/29 37.41 ± 11.37 24 (64.9%) 9 (24.3%) 4 (10.8%) 6 (16.2%) 15 (40.5%)
21/34 40.13 ± 12.08 36 (65.4%) 16 (29.1%) 3 (5.5%) 8 (14.5%) 20 (36.4%)
0.094 0.276 0.954 0.614 0.342 0.827 0.214
Table 2 LD analyses for BDNF gene in a Brazilian bipolar sample. L1
rs4923463 rs4923463 rs4923463 rs6265 rs6265 rs2049045
rs6265 rs2049045 rs7103411 rs2049045 rs7103411 rs7103411
0.727 0.683 0.819 0.898 1.0 1.0
8.36 7.21 11.8 16.41 15.52 15.76
0.404 0.374 0.535 0.769 0.608 0.639
Genotype and allele frequencies of BDNF polymorphisms in the AIM+ and AIM− groups are shown in Table 3. No signiﬁcant differences were found between both groups. Haplotype analysis shows only a trend to a positive correlation (P-value = 0.068) when alleles of rs2049045 (G/C polymorphism) and rs7103411 (T/C polymorphism) were combined. 4. Discussion Our study is the ﬁrst attempt, to our knowledge, to study the association of antidepressant-induced mania with BDNF polymorphisms in a sample comprised only of self-assigned White-Brazilian individuals. Our results show that in the Brazilian sample the data are in agreement with the report by Zai et al. (2007) and do not support the hypothesis of BDNF polymorphisms playing a role in antidepressantinduced mania. It is interesting to point out that our sample is larger than that of Zai's study and, therefore, has a higher power to detect a signiﬁcant effect with a genotypic relative risk.
Table 3 Genotype and allele frequencies for the BDNF polymorphisms in the groups AIM+ vs. AIM−. BDNF polymorphisms rs4923463 Alleles G A Genotype GG AG AA rs6265 Alleles A G Genotype AA GA GG rs2049045 Alleles G C Genotype GG CG CC rs7103411 Alleles T C Genotype TT CT CC
Total sample (n = 92)
AIM+ group (n = 37)
AIM− group (n = 55)
3 23 66
1 8 28
2 15 38
3 17 72
1 8 28
2 9 44
70 20 2
29 8 0
41 12 2
61 27 4
23 12 2
38 15 2
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A very important limitation of our study is the retrospective design, carrying all the inherent limitations of these types of studies. An ideal study should use initially drug-naive depressive bipolar patients prescribed antidepressants and mood stabilizers or a placebo, in a double blind and random basis; however, this is hardly feasible and surely would raise enormous ethical considerations. In all case– control psychiatric genetic studies, we must be aware of false-positive and false-negative ﬁndings due to ethnic stratiﬁcation. Our sample was comprised only of self-assigned White-Brazilian individuals. However, as recently demonstrated, race as determined by self and/or clinical evaluation is a poor predictor of ancestry in Brazil and an ethnic stratiﬁcation bias cannot be ruled out (Parra et al., 2003). In summary, the results of this study demonstrate that, although some studies suggest a role of the BDNF gene in BD susceptibility and in a manic state (Neves-Pereira et al., 2002; Sklar et al., 2002; Hashimoto et al., 2004; Tsai, 2004), our data are in disagreement with at least the manic-hypothesis. A more deﬁnitive understanding of these observations must await further studies that include a larger number of subjects and employ prospective designs.
Acknowledgements This work was supported by CNPq and FAPEMIG.
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