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 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 39  |  Issue : 3  |  Page : 149-155

Analysis of human platelets brain-derived neurotrophic factor as a predictor of response in depressed patients


1 Department of Neuropsychiatry, Faculty of Medicine, Tanta University, Tanta, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
3 Department of Internal Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
4 Department of Emergency Hospitals, Faculty of Medicine, Mansoura University, Mansoura, Egypt

Date of Submission14-Apr-2014
Date of Acceptance13-Oct-2014
Date of Web Publication31-Dec-2014

Correspondence Address:
Abdulrahman Fahmi Alshaik
Department of Emergency Hospitals, Faculty of Medicine, Mansoura University, Algomhouria Street, Mansoura 35516
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-1067.148248

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  Abstract 

Background Despite the significant progress in the management of major depressive disorder, little is known about the biological alterations that underlie the pathophysiology or the treatment of depression. Previous studies show that the brain-derived neurotrophic factor (BDNF) may play a role in the pathophysiology of major depressive disorders. Assuming that BDNF may be implicated in the etiology of depression, we examined BDNF concentrations in patients with major depressive disorder and its correlation with therapeutic response to fluoxetine therapy.
Patients and methods This study included 40 depressed patients (25 women and 15 men) and 20 healthy individuals (11 women and nine men) as a control group selected to match the study group in age and sex. All patients were subjected a semistructured clinical interview of DSM-IV-TR for the diagnosis of major depressive disorder, assessment of severity of depression using the 16-item Hamilton Rating Scale of Depression before treatment and 8 weeks after fluoxetine treatment, and estimation of the level of BDNF before treatment and 8 weeks after antidepressant treatment.
Results Before treatment, the concentrations of BDNF were significantly lower in depressed patients than in the control participants. After treatment, a significant increase in the BDNF concentration occurred, with no significant difference from the control group. Serum BDNF levels in patients with poor response (17.58 ± 4.99 ng/ml) were significantly lower than those of the patients with good response (28.88 ± 7.81 ng/ml; t = 5.48, P = 0.001). However, there were no significant differences in both groups of patients compared with the normal controls (21.60 ± 8.04).
Conclusion BDNFs drug-free depressed patients are lower than those of healthy controls and we propose that low BDNF levels might reflect failure of neuronal plasticity in depression. Also, The increase in BDNF after antidepressant therapy could be considered a good predictor of response to antidepressant therapy and might contribute toward the therapeutic response of patients with major depressive disorder.

Keywords: brain-derived neurotrophic factor, depressed patients, platelets


How to cite this article:
Eissa MA, Mansour AH, Ayyad RS, Ragab M, Alshaik AF. Analysis of human platelets brain-derived neurotrophic factor as a predictor of response in depressed patients. Egypt J Haematol 2014;39:149-55

How to cite this URL:
Eissa MA, Mansour AH, Ayyad RS, Ragab M, Alshaik AF. Analysis of human platelets brain-derived neurotrophic factor as a predictor of response in depressed patients. Egypt J Haematol [serial online] 2014 [cited 2019 Dec 10];39:149-55. Available from: http://www.ehj.eg.net/text.asp?2014/39/3/149/148248


  Introduction Top


Significant progress has been made in our ability to treat depression, but not all depressed patients respond to available antidepressants and the therapeutic response requires several weeks or months of treatment [1],[2] . In addition, still, very little is known about the neurobiological alterations that underlie the pathophysiology or the treatment of depression. In recent years, research has been focused on sites beyond the level of monoamines and receptors to examine potential postreceptor mechanisms in the action of antidepressant treatment. These studies have identified adaptations of intracellular signaling proteins and target genes that could contribute toward the action of antidepressant treatment [2],[3],[4] . One target gene of antidepressant treatment is brain-derived neurotrophic factor (BDNF). Neurotrophins, and in particular BDNF, play important roles in the proliferation, differentiation, and survival of neurons during development as well as in the synaptic activity and plasticity in many groups of mature neurons [5] . Furthermore, BDNF protects against stress-induced neuronal damage, and it might affect neurogenesis in the hippocampus, which is believed to be involved in the pathogenesis of mood disorders [6] . The possibility that BDNF is also involved in the pathophysiology of stress-related mood disorders is supported by reports that BDNF expression is decreased by exposure to stress [7],[8] . Clinical brain-imaging studies show that the volume of the hippocampus is decreased in depressed patients, consistent with the possibility of reduced neurotrophic factor support or synaptic remodeling in depression [9],[10] ; also, BDNF has been shown to play a major role in reducing neuroplasticity in aged rats [10] . Antidepressant treatment increases the expression of BDNF in limbic structures, most notably the hippocampus [11],[12],[13] . Upregulation of BDNF occurs in response to chronic but not acute antidepressant treatment, consistent with the time course for the therapeutic action of antidepressants. These findings suggest that BDNF plays a critical role in the pathophysiology of mood disorders and in the activity of therapeutic agents in patients with mood disorders [6] .

The source of BDNF in the peripheral blood and its regulation is still poorly understood. Studies showed that BDNF protein is present in the human platelets and is released upon agonist stimulation such as thrombin, collagen, and the Ca ++ ionophore. Thus, platelets may have a nonreleasable pool of BDNF [14] or the released BDNF binds to a recognition site on the platelet surface and is internalized, as in serotonin. Platelets appear to bind, store, and release BDNF upon activation at the site of traumatic injury to facilitate repair of peripheral nerves or other tissues [15] .

Assuming that BDNF may be implicated in the etiology of depression, and little is known about biological predictors of treatment response in major depressive disorders, this study was designed to detect the BDNF levels in patients with major depressive disorder and to assess its correlation with therapeutic response to antidepressant therapy. Our study evaluated the pretreatment and post-treatment levels of BDNF in a group of depressed patients and compared them with healthy controls.


  Patients and methods Top


This study was carried out in Mansoura Internal Medicine Hospital and Tanta n0 europsychiatry d0 epartment. It included 40 patients (25 women and 15 men) diagnosed with major depressive disorder. The study also included 20 healthy individuals (11 women and nine men) as a control selected to match the study group in age and sex.

The exclusion criteria for all patients and controls were as follows:

  1. Substance abuse within the past 3 months, or substance dependence within the past year.
  2. Schizoaffective disorder, schizophrenia, dementia, seizure disorder, eating disorders, or adjustment disorder with depressed features.
  3. Currently on active or maintenance chemotherapy.
  4. Used electroconvulsive therapy (ECT) within the past 3 months.
  5. Used oral or inhaled steroids within the last 2 months.
  6. Used oral antipsychotics within the past 4 weeks, depot antipsychotic within the previous 6 months, or mood stabilizers within the previous 4 weeks.


The Ethics Committee of Mansoura Faculty of Medicine approved the study protocol.

All participants signed an informed consent before testing was commenced. All patients were subjected to the following:

  1. Diagnosis of major depressive disorder by a semistructured clinical interview of DSM-IV-TR [16] .
  2. Assessment of severity of depression using the 16-item Hamilton Rating Scale of Depression (HRSD) [17] before treatment and 8 weeks after fluoxetine treatment. After treatment, we defined response to therapy as at least a 50% reduction from the baseline HRSD scores of depression, partial response as a 25-50% reduction in scores, and nonresponse as less than a 25% reduction in scores [18],[19] .
  3. Complete blood picture using Coulter-ACT diff (Beckman Coulter Inc., Hialeah, CA, USA), stressing on platelet count [20] .
  4. Estimation of the level of BDNF in serum, plasma, and platelets in patients before treatment and 8 weeks after antidepressant treatment and in control participants. Five milliliter venous blood was withdrawn by venipuncture from each participant for serum, plasma, and platelet BDNF:

    1. In a dry and clean centrifuge tube, 2 ml of blood was placed and the tubes were incubated in a 37°C incubator for 30 min and then centrifuged. Serum was stored at −20°C until assayed.
    2. The remaining 3 ml blood was added to 50 μl EDTA as an anticoagulant (1 ml blood for complete blood picture and platelet BDNF, and the other 2 ml centrifuged for plasma BDNF).
    3. Serum and plasma BDNF levels were determined by a commercially available enzyme-linked immunosorbent assay (ELISA) method using the BDNF Emax Immunoassay System Kit. The kits was supplied by Promega (Madison, Wisconsin, USA) with a minimum detectable level less than 8.1 pg/ml [21] . The assay depends on competition between a fixed amount of BDNF labeled with horseradish peroxides with unlabeled BDNF present in the extracted complexes for a limited number of binding sites coated. After washing and subsequent addition of chromometric substrate, the amount of this substrate is determined colorimetrically by measuring the absorbance, which is inversely proportional to the BDNF concentration.
    4. Platelet BDNF was calculated by subtracting plasma BDNF from serum BDNF, and dividing the result by the platelet count [22] .


Statistical analysis

The raw data were fed to the computer program Minitab0 software (release 16.1, Coventry, UK). The χ2 -test was used for comparison between the two groups of qualitative data. A two-sample t-test was used to compare the two means of two different groups. A paired t-test was used to compare two means in the same group before and after treatment. To assess the correlation between clinical variables, the Pearson correlation test was used. Results were considered significant at P value 0.05 or less.


  Results Top


No significant difference was found between the mean age of depressed patients (34.7 ± 11.90) and the control participants (29.95 ± 8.96; t = 1.73, P = 0.089). No significant difference was found in sex (χ2 = 0.0313, P = 0.576) or the mean number of years of education (patients 8.68 ± 4.88, control 10.35 ± 3.20; t = 1.59, P = 0.117).

The mean duration of illness was 4.85 ± 4.61 years ([Table 1]).
Table 1 Demographic variables of patients and controls

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Depression severity by Hamilton Rating Scale of Depression before and after treatment in depressed patients

In depressed patients, before fluoxetine treatment, the mean score of HRSD was 22.325 ± 3.377. After 8 weeks of fluoxetine treatment with a mean dose of 43 ± 17.86, a significant reduction in HRSD scores to 9.775 ± 3.076 (t = 16.94, P = 0.001) was observed ([Table 2] and [Figure 1]).
Figure 1 Hamilton Rating Scale of Depression (HRSD) in depressed patients before and after treatment.

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Table 2 Severity of depression by Hamilton Rating Scale of Depression and brain-derived neurotrophic factor before and after treatment

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Brain-derived neurotrophic factor before and after treatment in depressed patients

Before fluoxetine treatment, the mean serum level of BDNF was 12 ± 6.39, that of platelet BDNF was 93.1 ± 27.5, and that of plasma BDNF was 83.5 ± 20.8. A significant increase in the serum (25.49 ± 8.76; t = 11.04, P = 0.001) and plasma level (165 ± 118; t = 4.30, P = 0.001) of BDNF was found after chronic fluoxetine treatment; however, there was no significant difference in platelet BDNF (92.1 ± 18.2; t = 0.18, P = 0.859) ([Table 2] and [Figure 2]).
Figure 2 Brain-derived neurotrophic factor (BDNF) in depressed patients before and after treatment.

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Brain-derived neurotrophic factor in control and depressed patients before treatment

Before fluoxetine treatment, the mean serum (12.00 ± 6.39) and plasma BDNF (83.5 ± 20.8) was found to be significantly lower in depressed patients than the mean serum (21.60 ± 8.04; t = 4.66, P = 0.0001) and plasma BDNF (171.1 ± 75; t = 5.12, P = 0.001) of the control group. There was no significant difference between patients and controls in the mean platelet BDNF (93.1 ± 27.5 and 78.8 ± 30.5, respectively; t = 1.76, P = 0.087) ([Table 3] and [Figure 3]).
Figure 3 Brain-derived neurotrophic factor (BDNF) in depressed patients and the control group before treatment.

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Table 3 Brain-derived neurotrophic factor in depressed patients and controls before treatment

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Brain-derived neurotrophic factor in control and depressed patients after treatment

After 8 weeks of fluoxetine treatment, a significant increase in serum (mean 25.49 ± 8.76) and plasma BDNF (mean 165 ± 118) was detected in depressed patients, with no significant difference from serum (t = 1.71, P = 0.094) and plasma BDNF (t = 0.24, P = 0.809) of the control group. There was no significant difference between patients (mean 92.1 ± 18.2) and controls (mean 78.8 ± 30.5) in platelet BDNF (t = 1.80, P = 0.084) ([Table 4] and [Figure 4]).
Figure 4 Brain-derived neurotrophic factor (BDNF) in depressed patients and the control group after treatment.

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Table 4 Brain-derived neurotrophic factor in depressed patients and controls after treatment

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Serum brain-derived neurotrophic factor in good and poor responders

The mean serum BDNF of poor responders (17.58 ± 4.99) was significantly lower than that of good responders (28.88 ± 7.81; t = 5.48, P = 0.001) ([Table 5]).
Table 5 Brain-derived neurotrophic factor in good and poor responders to treatment in depressed patients

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However, there were no significant differences in both groups of patients compared with the normal controls ([Table 4]).

Correlation between serum brain-derived neurotrophic factor and Hamilton Rating Scale of Depression scores in depressed patients after treatment

A significant negative correlation was found between the scores of HRSD (mean 9.775 ± 3.076) and the serum level of BDNF (25.49 ± 8.76; r = −0.893, P = 0.001); thus, the higher the level of serum BDNF, the lower the HRSD scores ([Table 6]).
Table 6 Pearson correlation between brain-derived neurotrophic factor and Hamilton Rating Scale of Depression scores in depressed patients after treatment

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  Discussion Top


Neurotrophins have been identified as a new lead for a deeper understanding of mood disorders. This hypothesis has emerged from experimental evidence suggesting that antidepressant drugs might work by a neuroprotective effect through the stimulation of neurotrophin expression in distinct regions of the CNS [23],[24] .

Platelets, brain neurons, and vascular endothelial cells are considered candidate sources of BDNF. A major source of the serum BDNF are platelets, which bind, store, and release BDNF upon activation and in response to coagulation stimuli [25],[26] . As platelets and neurons develop from a common embryonic precursor in the neural crest [27] , the peripheral BDNF concentration could possibly reflect the central neurotransmission state [28] . A parallel BDNF brain and serum situation is underlined by the finding of Karege et al. [29] , who reported a positive correlation between the brain and serum BDNF levels in rats, which underwent similar changes during maturation and aging processes. Moreover, findings that BDNF in the periphery crosses the blood-brain barrier by a high-capacity, saturable transport system [29] and evidence that plasma BDNF levels do not differ from CSF levels suggest that peripheral changes may also reflect central processes [30] .

Our study evaluated the pretreatment and post-treatment levels of BDNF in a group of depressed patients and compared them with healthy controls.

This study showed that the baseline BDNF in depressed patients is significantly lower than that of the control group. Many studies carried out in depressed patients have shown that BDNF expression is decreased [31],[32],[33],[34] . Low BDNF levels might reflect a genetic profile, which is linked to susceptibility to depression and therefore BDNF serum concentrations could serve as a risk marker for depression [35] . Another possibility that may explain our results would be that BDNF serum concentrations are altered secondarily in a stress-dependent manner. Stress can precipitate and exacerbate depression and may cause neuronal atrophy and death, especially in the hippocampus [36],[37] . Thus, a stress-induced BDNF reduction would inhibit the protective and trophic BDNF effects in the hippocampus. Accordingly, a stress-induced reduction in hippocampal volumes [38] and BDNF may be central to the development of depressive mood states [39] .

Existing data from animal models support a role for BDNF in the pathophysiology of depression. Prolonged exposure to several stressors, including immobilization stress, forced-swim stress as well as conditioned footshock, results in the downregulation of BDNF expression in the hippocampus [7],[40] . Animal models such as learned helplessness also result in a decrease in hippocampal BDNF expression [41],[42] .

In this study, chronic antidepressant treatment with fluoxetine led to increased levels of BDNF so that there eventually, there was no significant difference between the depressed patients and the controls. The serum BDNF levels of the patients with poor response (no or partial response) were significantly lower than those of the patients with good response. However, there were no significant differences in both groups of patients compared with the normal controls. So, it seems very important for an antidepressant to increase the BDNF to produce an antidepressant response. Santarelli et al. [43] were the first to indicate that the increased neurogenesis in the hippocampus is essential for an antidepressant response to occur [42] . The reported antidepressant-induced neurogenesis in the hippocampus may be central to the antidepressive properties of antidepressant medications, and this neurogenesis is possibly at least partly because of BDNF accumulation.

The response to antidepressant therapy evidenced by a reduction in the scores of HRSD was correlated negatively with the increase in the serum level of BDNF. Thus, the higher the serum level of BDNF, the more the improvement in depressive symptoms, evidenced by the lower scores of HRSD.

It was found that several classes of antidepressants increase the expression of BDNF in rat brain [6],[44],[45],[46] as well as in depressed patients [35],[36],[47],[46],[47],[48],[49],[50],[51] . In another study, it was found that physical exercise and antidepressant treatment increase the transcription of BDNF [45] . However, administration of BDNF increases adult neurogenesis in the hippocampus [52] . This suggests that the effect of antidepressants on neurogenesis may be mediated by BDNF, through its signaling pathway, particularly the mitogen-activated protein kinase pathway [53] , and transgenic mice with reduced BDNF signaling in the brain are insensitive to antidepressants in behavioral tests [54] . Moreover, BDNF signaling plays a role in the differentiation and survival of neuronal progenitor cells [55],[56] .

An augmentation of serotonergic activity within various brain areas following an infusion of BDNF into the midbrain has been reported recently. This serotonergic activity is because of the modulation of the serotonin transporter [57] .

Long-term antidepressant treatment has been shown to increase BDNF protein and mRNA levels, and this treatment also reverses the stress-induced downregulation of BDNF [6] . However, it has also been reported that the effect of antidepressants on BDNF gene expression may be biphasic and time dependent [46] . Exogenous administration of BDNF, either by the intracerebroventricular or by the intrahippocampal route, exerts antidepressant effects on multiple models of depression [58] . Clinically, there is increased BDNF immunoreactivity in patients treated with antidepressant medication [59] . Furthermore, the levels of BDNF were higher in the postmortem hippocampal tissue obtained from antidepressant-treated patients than those from untreated patients. Numerous clinical studies have found that chronic use of antidepressants increases serum BDNF levels in patients with depression [47] . Also, fluoxetine may potentially improve cognition in patients with vascular dementia, and this requires further investigation [60] .

It was found that the baseline BDNF was low in serum and plasma; however, platelet BDNF was found to be normal. After chronic antidepressant treatment, a significant increase in BDNF was detected in serum and plasma; meanwhile, platelet BDNF was not affected. Thus, there was no significant association between platelet BDNF in patients and control group. Fujimura et al. [27] established that platelets BDNF is neither produced by platelets nor by its precursors. However, BDNF is actively acquired by platelets from external sources and released by agonist stimulation. Our results suggest that an alteration in serum or plasma BDNF is not because of the change in blood BDNF, but is rather probably related to mechanisms of BDNF release. Secretion of BDNF seems to be independent of platelet reactivity; other mechanisms are therefore probably involved [48] . This means that the change in the BDNF level is unrelated to the BDNF stored inside the platelets, and sources other than platelet, possibly brain neurons, are responsible for increased BDNF.

Our study showed that BDNFs) of drug-free depressed patients are lower than those of healthy controls and proposed that low BDNF levels might reflect failure of neuronal plasticity in depression. After antidepressant treatment, the attenuated BDNF levels in depressed patients increase. Thus, the increase in BDNF after antidepressant therapy could be considered a good predictor of response to antidepressant therapy and might contribute toward the therapeutic response of patients with major depressive disorder.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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