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Aim: Recent studies suggested a role of brain-derived neurotrophic factor in depression. While BDNF levels are lower in depressed patients, antidepressant treatment increases serum BDNF levels of depressed patients. Our study aims to test the effect of antidepressant treatment on serum BDNF levels in patients with depressive disorder.
Methods: Twenty three patients (-- women, -- men) diagnosed with first depressive episode according ICD-10 are included in the study. The severity of depression was assessed with Hamilton Depression Rating Scale (HDRS). The control group consisted of 23 age- and sex-matched subjects without history of any psychiatric disorder. Blood samples were collected at the baseline and after achieved remission (decrease of minimum 50% on HDRS). Results: Before antidepressant treatment the mean serum BDNF level was 13.15 Â± 6.75 ng/ml and the mean HDRS score was 28.52Â±4.02. Serum BDNF levels of the depressed patients were significantly lower than in the control group (25.95Â±9.17 ng/ml). At the end of the study, the mean serum BDNF level was 24.73Â±11.80 ng/ml whereas the mean HDRS score was 7.04Â±3.15. From the baseline to the remission after 8 weeks of treatment, the increase in serum BDNF level and the decrease in HDRS score were statistically significant, respectively. When we compared the serum BDNF levels of depressed patients at remission to that of the controls, there was no statistically significant difference. Conclusion: Our study suggests that low BDNF levels may play a pivotal role in the pathophysiology of MDD and that antidepressants may increase BDNF in depressed patients, which may be considered as a nonspecific peripheral marker of depression.
Key words: Depressive disorder, BDNF
Depressive disorder is a serious illness that affects 17% of population in some life period, which places a heavy social and economic burden over society. [Kessler RC, 1994, Belmaker RH, 2008] Life-time prevalence of depressive disorder is estimated between 6% and 16%. The etiology of depressive disorder is not completely understood, but there is evidence in support of complex interactions of biological, genetic, psychosocial and environmental factors. The depression risk is associated with combination of many etiological factors. [Costello EJ, 2002; Merikangas KR, 2002; Nestler EJ, 2002]. As well as the etiology, the precise neurobiology that underlies mood disorders is currently not precisely determined.
Brain-derrived neurotrophic factor (BDNF) involvemnet in depressive disorder has been in focus of intensive research for the last decade. BDNF belongs to a neurotrophic family of growth factors and affects neuronal survival and function. BDNF is detectable in blood, although its concentration in brain tissue is higher. [Radka SF, 1996; Yamamoto H, 1990]
It has been reported that BDNF may pass blood-brain barrier, [Pan W, 1998] and that BDNF serum and brain levels go through similar changes in maturation and ageing in rats, [Karege F, 2002] which indicates that serum BDNF levels reflect brain BDNF levels.
Karege et al. were the first to report significantly reduced serum BDNF levels in untreated patients with major depressive disorder, and that serum BDNF levels are in negative correlation with depression severity. Shimizu et al. reported that BDNF levels in patients with major depressive disorder who were not treated with antidepressants, are significantly lower than those in patients that were treated and healthy controls; they have also shown that serum levels of BDNF are in negative correlation with severity od depression. [Shimizu E, 2003]
After Karege et al., several studies demonstrated lower BDNF levels in patients with major depressive disorder and increase in BDNF levels in patients treated with antidepressants. [Piccinni A, 2010; Gervasoni N, 2005; Aydemir O, 2006; Yoshimura R, 2007; Karege F b, 2005; Aydemir O, 2007; Huang TL, 2007; Gonul AS, 2005; Monteleone P, 2008].
Sen et al. meta analysis provides strong evidence that BDNF levels are lower in depressive patients compared to healthy controls (p < 6.8 Ñ… 10-8), and that BDNF levels are significantly increased (p = 0.003) after antidepressive treatment. [Sen S, 2008] Brunoni et al. meta-analysis, similarly showed that BDNF levels are significantly increased after antidepressive treatment (effect size: 0.62), and that significant correlation exists between (p = 0.02) BDNF changes and changes in depression rating scale results [Brunoni AR, 2008].
Materials and methods
Twenty three patients (11 women, 12 men) diagnosed with first depressive episode according ICD-10 were included in this study. Average age of the experimental group was 44.22 years. The severity of depression was assessed with Hamilton Depression Rating Scale (HDRS). The control group consisted of 23 age- and sex-matched subjects without any psychiatric disorder (average age 44.04 years). Blood samples were collected at the baseline and after achieved remission (decrease of minimum 50% on HDRS, average time between two measurements 8 weeks). Serum BDNF levels were measured using the BDNF Emax Immunoassay System kit (Promega; Madison, WI, USA) according to the manufacturer's instructions.
In short, 96-well microplates were coated with anti-BDNF monoclonal antibody and incubated at 4 Â°C for 18 h. The plates were incubated in a blocking buffer for 1 h at room temperature. The samples diluted with assay buffer 100-times and BDNF standards were kept at room temperature under conditions of horizontal shaking for 2 h, followed by washing with the appropriate washing buffer. The plates were incubated with antihuman BDNF polyclonal antibody at room temperature for 2 h and washed with the washing buffer. The plates were then incubated with anti-IgY antibody conjugated to horseradish peroxidase for 1 h at room temperature, and incubated in peroxidase substrate and tetramethylbenzidine solution to induce a color reaction. The reaction was stopped with 1 mol/L hydrochloric acid. The absorbance at 450 nm was measured with an Human Elysis Uno automated microplate reader. Measurements were performed in duplicate. The standard curve was linear from 5 pg/mL to 5000 pg/mL. Cross-reactivity to related neurotrophins (NT-3, NT-4, NGF) was less than 3%. Intra- and inter-assay coefficients of variation were 5% and 7%, respectively. The recovery rate of the exogenous added BDNF in the measured plasma samples was more than 95%. This study was approved by the Ethics Committee of the Medical Faculty, University of Sts. Cyril and Methodius Skopje, and written informed consent was obtained from all participants.
Average Â± SD
13.15 Â± 6.75
BDNF 1 - BDNF serum levels in depressed patients before treatment
BDNF 2 - BDNF serum levels in depressed patients after treatment
BDNF C - BDNF serum levels in control group
HDRS 1 - Hamilton Depression Rating Scale results in depressed patients before treatment
HDRS 2 - Hamilton Depression Rating Scale results in depressed patients after treatment
In this study we examined the efect of first depressive episode over the serum BDNF level as well as the efect of chronic antidepressive treatment.
We have found a statistical significance (p=0.000091) between serum BDNF levels in depressed patients at baseline, compared to BDNF levels after treatment, and compared to healthy control subjects (p<0.5).
Furthermore, antidepressant treatment increased BDNF levels in depressed patients (24.73 Â± 11.80) close to the levels of healthy controls (25.95 Â± 9.17) and there is no statistically significant difference between serum BDNF levels (p=0.349).
This pilot study shows that chronic antidepressive treatment can significantly increase low serum BDNF levels in patients with depressive disorder when patients achieved remission. When compared with control group, serum BDNF level is lower in untreated depressive patients, and antidepressive treatment increases serum BDNF level in depressive patients to the level of healthy controls.
These findings correspond to previously published studies on serum BDNF levels, after Karege et al. 2002 were the first to publish lower serum BDNF levels in depressive patients, free of antidepressive treatment for 3 weeks.
We found very week negative correlation between serum BDNF levels and the length of antidepressive treatment (r = -0.162).
It appears that BDNF levels increase while depressive symptoms decline. In our sample there is weak negative correlation between BDNF levels before treatment and HDRS before treatment (r = -0.168) and between BDNF levels after treatment and HDRS after treatment (r = -0.225). There is also weak correlation between BDNF increase and HDRS decline (r = -0.157).
These results may indicate that low serum BDNF level may be important feature of depression. The finding of lower BDNF levels in depressed patients before treatment compared to BDNF levels after treatment indicates that this neurotrophic factor has pivotal role in depressive disorder.
Our patients all suffered of first major depression episode that in average lasted 3.96 months before antidepressive treatment. Decreased levels of BDNF indicate that even first signs od depression have an impact on the neurons. Antidepressive treatment appears to normalize BDNF levels, so it might be safe to assume that earlier pharmacological intervention is neuroprotective.
Our findings indicate that BDNF levels are significantly lower in untreated depressive patients compared to healthy controls, and that those levels increase after antidepressant treatment. These results can be interpreted as effects of antidepressant treatment over the neuroplasticity and depressive symptoms.
The effects of different antidepressive medications are associated with BDNF increase, which may indicate that BDNF is a "common final pathway" for different antidepressive approaches.