Neurotrophic factors are central to many functions in the central nervous system, with critical roles in the neuronal survival, migration, synaptogenesis and plasticity of neuronal networks. Of these, brain-derived neurotrophic factor (BDNF) has particularly been investigated intensively in the regulation of mood disorders and also in relation to antidepressant effects. Several lines of converging evidence indicate that BDNF plays a role in depression and in the mechanism of antidepressant function (Castren et al., 2007).
Normal BDNF signalling is necessary for antidepressant drug action. Antidepressant treatments increase BDNF synthesis and BDNF signalling in the hippocampus and prefrontal cortex (Nestler et al., 2002; Castren et al., 2007). It has been shown that the BDNF serum level is reduced in depressed patients and that a restoration is observed after antidepressant treatment (Nestler et al., 2002; Castren et al., 2007; Terracciano et al., 2011). The role of BDNF both in the aetiology of depression and in the context of antidepressant response has therefore been suggested to be important. Thus, the BDNF gene is one candidate gene related to depression and in influencing treatment response to antidepressants.
Several studies have investigated different BDNF gene single nucleotide polymorphisms (SNPs) in the treatment response to antidepressants in major depressive disorder (MDD); some studies have found that BDNF gene polymorphisms are associated with depression and treatment response to antidepressants, but the results are inconsistent. The most studied BDNF polymorphism is the Val66Met (rs6265) polymorphism. Recently, rs11030101 has been reported to be associated with MDD and rs61888800 with antidepressant treatment response. (Licinio et al., 2009; Chi et al., 2010; Kato and Serretti, 2010; Verhagen et al., 2010; Yoshimura et al., 2011).
In this study, the primary objective was to investigate the association of two BDNF SNPs, rs11030101 and rs61888800, in the treatment response to selective serotonin reuptake inhibitor (SSRI) medication in Finnish patients with MDD. A secondary objective was to investigate whether patients with MDD have a different distribution of these two SNPs when compared with healthy controls.
Materials and methods
We recruited 106 outpatients of Finnish origin, aged 18–72 years, who fulfilled the criteria for major depression of the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. The patients were recruited from a larger sample of primary and secondary outpatient services as well as through newspaper advertisements. All patients were diagnosed and interviewed by a psychiatrist and the severity of their depression was evaluated using the Montgomery-Åsberg Depression Rating Scale (MADRS). Patients with a baseline MADRS score of 20 or more were eligible for the study. Patients with severe somatic diseases or medication affecting their mood, other significant psychiatric disorders, such as bipolar disorder, psychosis or severe personality disorders or alcohol or substance dependency were excluded. Altogether, 86 patients completed the entire study according to the study protocol. Control DNA samples (n=386) were obtained from healthy Finnish blood donors.
At the first study visit, citalopram, fluoxetine or paroxetine was initiated at the investigators’ discretion. Anxiolytics and sedative hypnotics as an adjuvant treatment and other medications for concomitant general medical conditions were allowed. Patients were seen again at 3 and 6 weeks after taking the study medication. Compliance was evaluated by a medication diary kept by the patient. Treatment was deemed to have taken place if the patient had taken the medication on at least 80% of the days of the study period. After 6 weeks’ treatment, the response was checked using the MADRS. The primary outcomes of the treatment were remission, defined by an exit score of 7 or less, and response, defined by a reduction of at least 50% on the MADRS.
All patients provided written informed consent to participate in the clinical study. The local ethics committees reviewed and approved the study protocol.
Genomic DNA was extracted from peripheral blood leucocytes using the QIAamp DNA Blood Minikit and automated biorobot M48 extraction (Qiagen, Hilden, Germany). BDNF gene alterations rs11030101 and rs61888800 were genotyped using Taqman SNP Genotyping Assays C___1751785_10 and C__89097203_10, respectively, and the ABI Prism 7900HT Sequence Detection System (Applied Biosystems, Foster City, California, USA). Ten random samples were run as duplicates. No discrepancies were found.
Statistical methods/data analysis
The results for MADRS starting points, age and doses of SSRI are given as mean and SD. The statistical significance of the differences between the nonremission and the remission group and also between the response and the nonresponse group was analysed using an independent-samples t-test. Pearson χ2-tests were used to compare the BDNF rs11030101 and the rs61888800 genotypes between the remission and the nonremission groups and between the responders and the nonresponders and controls. A P-value less than 0.05 was considered statistically significant. The computations were carried out using SPSS for Windows, version 14.0 (SPSS Inc., Chicago, Illinois, USA), statistical software.
Demographic data of the patients and controls are presented in Table 1. The MADRS starting points were slightly higher in the nonremission group than in the remission group. The MADRS scores were not associated with rs11030101 or rs61888800. See Table 2 for details of the selected clinical data. In the distribution of the two BDNF polymorphisms studied, no statistically significant differences were found (Table 3).
Theoretically, the BDNF gene is a strong candidate to influence the antidepressant response and/or to play a role in the aetiology of depression. Although in some studies the BDNF gene has been associated with depression, the current knowledge does not consistently link BDNF gene variants to the aetiology of depression. In antidepressant treatment response, the BDNF gene has been investigated in several patient populations. The most studied polymorphism of this gene in the context of antidepressant response is the Val66Met (rs6265) polymorphism. Some studies have found associations with this functional polymorphism, whereas others have not (Licinio et al., 2009; Chi et al., 2010; Kato and Serretti, 2010; Verhagen et al., 2010; Yoshimura et al., 2011). In addition, a genome-wide pharmacogenetic association study (Uher et al., 2010) did not find associations of BDNF gene variants with antidepressant response.
Our study did not find associations of these two BDNF polymorphisms with patients with MDD when compared with healthy controls and/or in treatment response to SSRI medication. We studied two polymorphisms, rs11030101 and rs61888800, which cover only a minority of the genetic variation in the BDNF gene. Interestingly, a recent large case–control study (Licinio et al., 2009) investigating 130 SNPs in the BDNF gene in association with the MDD and antidepressant treatment response found an association of the rs61888800 SNP, which we could not replicate in our study. The main limitation of our study is the small sample size, which markedly reduces the power to detect small or moderate effects. Another limitation of the study is that the controls were not screened psychiatrically. Therefore, 5% of the controls may be expected to have depression. However, it is important to gather information in different patient populations and it is useful that negative findings are also reported to prevent publication bias and thus, for example, to generate a more reliable basis for meta-analysis.
We could not find any association with BDNF gene SNPs rs61888800 and rs11030101 in MDD and/or remission or treatment response to SSRI treatment among patients of Finnish origin with MDD.
This study was supported by a research grant from the Tampere University Hospital Medical Fund.
Conflicts of interest
There are no conflicts of interest.
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