[1]
442w
Selective serotonin reuptake inhibitors (SSRIs) are currently the first-line approach for the treatment of major depressive disorders due to both the efficacy of these drugs and the relatively small number of adverse effects associated with their use (Yoshimura et al., 2010). There is growing evidence indicating that BDNF may play a crucial role in mental disorders such as depression (Duman et al., 1997) and schizophrenia (Shoval and Weizman, 2005). Karege et al. (2002a) demonstrated that the serum BDNF levels of their drug-free patients were lower than those of controls, and Shimizu et al. (2003) found that serum BDNF levels of treated depressed patients do not differ from those of healthy controls. Aydemir et al. (2005) reported that serum BDNF levels are lower in depressed patients than in controls, and that treatment with antidepressant drugs for twelve weeks increases serum BDNF levels to those of healthy controls. Gonul et al. (2005) also reported that treatment with several antidepressant drugs for 8 weeks significantly increases serum BDNF levels to the level in control subjects. Such results have suggested that antidepressant drugs increase serum BDNF levels in depressed patients. There have been at least three meta-analyses of studies of blood BDNF levels in depressed patients (Sen et al., 2008;Brunoni et al., 2008;Bocchio-Chiavetto et al., 2010). The results of these previous investigations have generally revealed that blood BDNF levels in depressed patients are significantly lower than those of healthy subjects. Furthermore, treatment with antidepressants, electroconvulsive therapy, or repetitive transcranial magnetic stimulation all increase blood BDNF levels in depressed patients (Sen et al., 2008;Brunoni et al., 2008;Bocchio-Chiavetto et al., 2010). Taken together, these findings suggest that blood BDNF levels are a candidate biomarker for major depressive disorder. Moreover, such results provide support for the notion that the amelioration of this disease by antidepressant treatment might be associated with neuroplastic changes. The BDNF gene is an important candidate for elucidating the mechanism of action of antidepressants, because BDNF plays a significant role in the functioning of the serotonin system. The human BDNF gene maps to chromosome 11p13, and contains a functional 196G/A single nucleotide polymorphism (rs6265) known to cause an amino acid substitution from valine to methionine in exon I (Val66Met). The BDNF gene encodes a precursor peptide that is proteolytically cleaved to form the mature protein BDNF (Mowla et al., 2001). In the present study, we investigated the association between the BDNF Val66Met polymorphism and baseline serum BDNF levels in depressed patients. We also examined the treatment response to SSRIs (paroxetine or sertraline) and the BDNF Val66Met polymorphism. Finally, we examined the serum BDNF levels and the severity of the depressive state using a larger sample size.
[1]
260w
There were no differences between responders and nonresponders in terms of sex, age, number of depressive episodes, HAMD-17 scores at T0 and T8 or allele frequency. However, serum BDNF levels at T0 were significantly higher in nonresponders than in responders (Table 1). The genotypes of the 132 subjects were as follows: BDNF Val66Val, 59 patients; BDNF Val66Met, 54 patients; and BDNF Met66Met, 19 patients. The Val/Met allele frequencies were within the Hardy-Weinberg equilibrium (X 2 = 1.30; p = 0.255). The genotypes Val66Val, Val66Met, and Met66Met were present in 44.6%, 40.9%, and 14.3% of subjects, respectively. The logistic regression analysis of the relation between the rs6265 genotypes and the baseline HAMD-17 scores revealed no significant differences in the baseline HAMD-17 scores or the changes in the HAMD-17 scores at T0 or T8 between the two genotypes (Val/Val vs. Met carriers). No correlations were found between the two genotypes and the serum BDNF levels at T0 (Fig. 1). Logistic regression analysis between the HAMD-17 scores at T0 and serum BDNF levels at T0 adjusted by age demonstrated a negative correlation between the two factors. (SRC = -0.311, p = 0.0003) (Fig. 2). A negative correlation was also found between the changes in HAMD-17 scores at T0 and at T8 and the serum BDNF levels at T0 adjusted by age (SRC = -2.43, p = 0.0052). However, no correlation was observed between the changes in HAMD-17 scores at T0 and at T8 and the HAMD-17 scores at T0 adjusted by age. These results suggest that the two correlations described above were independent.
[1]
326w
The most important finding of the present study was the lack of difference in baseline serum BDNF levels between the subjects with the genotype BDNF Vla66Val and those with either BDNF Val66Met or BDNF Met66Met (Met carriers). Duncan et al. (2009) reported observing no association between the BDNF gene Val66Met polymorphism and serum BDNF in healthy volunteers. Zou et al. (2010) also reported that serum BDNF concentrations were not associated with genotype either in patients with post-stroke depression or healthy controls. In contrast, Ozan et al. (2010) demonstrated that Metcarrying subjects had reduced serum BDNF levels, irrespective of gender or depression. The results in the present study were basically in accordance with the results of Duncan et al. (2009) and Zou et al. (2010); however, our subjects were neither patients with post-stroke depression nor healthy volunteers. Taking these findings into account, it remains unclear whether BDNF Val66Met polymorphism is indeed associated with serum BDNF levels. Recently, Bhang et al. (2011) reported that healthy volunteers who were homozygous for S at 5-HTTLPR and the Met allele of the BDNF Val66Met polymorphism displayed significantly lower serum BDNF levels. Although the primary source of circulating BDNF remains unknown, platelets, brain neurons, and vascular endothelial cells are currently considered to be among the sources. It is known that BDNF crosses the blood-brain barrier (Pan et al., 1998), and BDNF levels in the brain and serum of rats have been shown to undergo similar changes during maturation and aging (Karege et al., 2002b). Furthermore, Lang et al. (2007) reported that serum BDNF concentrations reflect certain aspects of neuronal plasticity, as indicated by the association of BDNF levels with 2011) recently reported that blood and plasma BDNF levels reflect brain-tissue BDNF levels. Nonetheless, the extent to which peripheral levels of BDNF reflect brain levels of BDNF remains unknown. In consideration of all the findings to date, it appears that the relationship between peripheral BDNF dynamics and brain BDNF dynamics is quite complex.
[2]
192w
Another important finding of the present study was the lack of an association between the response to SSRIs and the presence of the BDNF Val66Met polymorphism. In a meta-analysis of the putative BDNF Val66Met polymorphism, Zou et al. (2010) demonstrated an association between this polymorphism and treatment response in patients with major depressive disorder. The authors of that study also revealed that Val66Met heterozygous patients exhibited a better treatment response rate than did Val66Val homozygote patients, especially in the Asian population. The distributions of the genotypes Val/Val, Val/Met, and Met/Met were 27.46%, 48.82%, and 23.72%, respectively, in Zou's study using Chinese samples (2010). In contrast, the distributions were 34.2%, 40.2%, and 25.6%, respectively, in Chi's study using Chinese samples (2010). The genotype distribution in the present study is in accordance with these two recent studies (Zou et al., 2010;Chi et al., 2010). Zou et al. (2010) reported that patients with major depressive disorder and Val/Val responded better to fluoxetine, and displayed fewer side effects, than did those with Val/Met and Me66Met. Chi et al. (2010) reported that patients with the Val/Val genotype had a significantly higher chance of responding to venlafaxine treatment.
[3]
124w
These results, taken together, suggest that the BDNF Val66Met polymorphism may play a major role in the efficacy, as well as the side effects, of fluoxetine in depressed Chinese patients. The results of the present study were not in accordance with the results of the study by Zou et al. (2010); the reason(s) for the discrepancies between these two studies remains unknown. However, factors that might have contributed to the disparate results include antidepressants, treatment periods (i.e., 6 weeks in Zou et al., 2010 vs. 8 weeks in the present study), and number of depressive episodes. Furthermore, in our study, only two BDNF Val66Met genotype groups were considered, i.e., Val66Val and Met carriers, due to the small number of subjects with the Met66Met genotype.
[4]
604w
Finally, using a larger sample in the present study, we reconfirmed our previous finding (Yoshimura et al., 2007) of a negative correlation between the HAMD score and serum BDNF. These findings suggest that the serum BDNF level might serve as a possible biomarker of the severity of depression. There are positive (Karege et al., 2002a;Shimizu et al., 2003;Gervasoni et al., 2005;Gonul et al., 2005;Zanardini et al., 2006;Yoshimura et al., 2007) and negative (Aydemir et al., 2005;Molendijk et al., 2010) data regarding the correlation between serum BDNF levels and depression symptomatology (HAMD scores). On the other hand, there are also several reports demonstrating no difference in serum or plasma BDNF levels between depressed patients and normal controls or between male and female subjects (Ziegenhorn et al, 2007;Lee and Kim, 2008;Basterzi et al, 2009). Ziegenhorn et al. (2007) observed a significant correlation between serum BDNF levels and platelet count, age and BDNF protein levels. We speculated that age might be a factor that could explain the discrepancy between the results of the above studies and those of the present study. The age of the depressed patients in the present study was relatively high in comparison with recently published BDNF studies (Ziegenhorn et al., 2007;Lee and Kim, 2008;Basterzi et al., 2009). To the best of our knowledge, there have been at least three meta-analyses for blood BDNF in depressed patients. The results showed that the blood BDNF levels in depressed patients were significantly lower than those in healthy controls. From these findings, it seems plausible that the serum or plasma levels of BDNF were decreased in depressed patients compared with controls. However, whether the serum plasma BDNF level reflects severity of depression remains controversial. It has been reported that age and gender influence serum BDNF levels (Trajkovska et al., 2007;Ozan et al., 2010;Bus et al., 2011). Previously, however, we observed no association between age or gender and serum BDNF levels (data not shown). Although the response rate to SSRIs was significantly higher in males than in females, we reconfirmed the result that no association was observed between the baseline serum BDNF levels and age or gender using a larger sample size of depressed patients. In addition, no associations were observed between serum BDNF levels and the BDNF polymorphisms between male and female patients in the present study (data not shown). Therefore, it is unclear whether gender differences in serum BDNF levels actually exist or if there is an association between the BDNF polymorphism and serum BDNF levels (Karege et al., 2002a;Shimizu et al., 2003;Huang and Lee, 2006;Basterzi et al., 2009). In our analyses of the two groups, we did not control for body mass index or smoking status, which might have influenced serum BDNF levels. In addition, cardiovascular conditions of the patients were only checked by electrocardiogram (ECG). Further studies controlling for BMI, smoking status, and cardiovascular disease will be needed to reconfirm these preliminary results. Even more importantly, recent studies have shown that the genetics of depression in the elderly are different than the genetics in younger patients (Kendler et al., 2008). In conclusion, the BDNF Val66Met polymorphism in depressed patients is associated neither with a particular response to SSRI treatment nor with baseline serum BDNF levels; however, serum BDNF levels appear to be a candidate marker for severity of depression. 15 20 25 30 35 HAMD-17 -5 0 5 10 15 20 25 30 35 40 45 baseline serum BDNF (ng/ml) Fig. 2. Negative correlation between baseline HAMD-17 scores T0 and serum BDNF levels at T0 in depressed patients. SRC = -0.311, p = 0.0003. T0: at baseline; T8: 8 weeks after treatment with SSRIs.
[1]
369w
In this study, 132 patients who met the DSM-IV-TR (American Psychiatric Association, 2000) criteria for major depressive disorder were enrolled. 54 of these patients were male and 78 were female (age range, 20-74 years; mean± S.D., 51± 15). All patients were physically healthy without any abnormality; checked with electrocardiogram; had no comorbidity with axis II psychiatric disorder, as confirmed by the Structured Clinical Interview for DSM-IV (SCID) (First et al., 1995); and had not taken any psychotropic medication within the month prior to the onset of the study. The patients were treated with only paroxetine or sertraline for 8 weeks at a dose ranging from 20 to 40 (mean ± S.D., 31 ± 11) mg/day or 25-100 (mean± S.D., 71± 14) mg/ day. The dosage of paroxetine varied among patients, and ethical considerations prevented the dose prescribed to individuals from being fixed. The patients' clinical improvement was evaluated by two experienced psychiatrists (R.Y. and W. U-N.) using the 17-item Hamilton Rating Scale for Depression (HAMD-17) before and 8 weeks after the administration of paroxetine or sertraline. Previous reports have classified patients with an at least 50% decrease in HAMD score as treatment responders; thus, all remaining patients in the present study who did not exhibit such a decrease in the HAMD-17 scores were considered to be non-responders (Yoshimura et al., 2009a,b). Blood samples drawn into plain tubes were obtained at times between 08.00 and 10.00, before the patients had eaten breakfast (approximately 13-15 h after the most recent dose of the drug had been taken). The blood sample collection was performed before (T0) and 8 weeks after treatment (T8) with paroxetine or sertraline. The serum samples were quickly separated in a centrifuge and stored at -80 °C until assayed. Genomic DNA was extracted from peripheral leukocytes using a QIAamp DNA Blood Kit (Qiagen, Tokyo, Japan) and was stored at -20 °C until used for analysis. Genotyping for the presence of the BDNF Val66Met polymorphism was performed using the TaqMan genotyping assay (Applied Biosystems, Foster City, CA, USA). The protocol of this study was approved by the Ethics Committee of the University of Occupational and Environmental Health. All patients consented to participate after having been informed of the study's purpose.
[2]
61w
Multiple logistic or regression analyses were used to adjust for possible confounding variables. In these analyses, the clinical response to SSRIs was set as the dependent variable, and gender, age at the time of recruitment, HAMD-17 scores at T0 or T8, SSRI dose equivalent to imipramine at T8, and rs6265 genotype (Val/Val vs. Met carriers) were set as the independent variables.