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Keywords:

  • brain-derived neurotrophic factor;
  • late-onset geriatric depression;
  • tissue-type plasminogen activator

Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENT
  7. REFERENCES

Aims:  Studies in the recent decade have shown that brain-derived neurotrophic factor (BDNF) may play an important role in the pathogenesis of major depressive disorder (MDD). Tissue-type plasminogen activator (tPA) has been implicated in the control of the direction of BDNF action. The aim of the study was therefore to investigate the changes of BDNF/tPA levels and their clinical meanings in geriatric depression.

Methods:  Plasma BDNF and tPA levels were measured in late-onset geriatric depression (LGD) before treatment (n = 24) and after 6 weeks of antidepressant treatment (n = 24) compared with control subjects (n = 30) using enzyme-linked immunosorbent assay. The severity of depression was assessed with the Hamilton Depression Rating Scale.

Results:  Baseline plasma BDNF and tPA levels were significantly lower in LGD patients compared to controls (P = 0.037 and P = 0.000, respectively). There was a heightening tendency of plasma BDNF level after treatment.

Conclusions:  Plasma BDNF and tPA levels are associated with LGD. The complex mechanism of BDNF and tPA in LGD should be further explored in future studies.

MAJOR DEPRESSIVE DISORDER (MDD) is a common disabling psychiatric illness, which is fast becoming a major public health problem throughout the world. In the ≥65 age group MDD has a very high prevalence, ranging from 6.5% to 9%.1 It is becoming a major public health problem because of personal suffering and high mortality.2

The cellular and molecular bases of MDD, however remain unclear. There are many hypotheses for depression such as serotonergic dysfunction, hippocampal neuroplasticity and neurogenesis disturbance, hyperactivity of the hypothalamic–pituitary–adrenal axis and association with hemostatic and/or inflammatory markers.3–5 The most popular hypothesis is the neurotrophin hypothesis of depression. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic family known to regulate neuronal plasticity and survival, may play an important role in the pathogenesis of MDD and in the mechanisms underlying antidepressant therapeutic action.6 Karege et al. first reported that plasma BDNF levels were decreased in depressive patients.7 Moreover, increasing evidence suggested that low plasma BDNF level, which had increased after antidepressant treatment, was significantly associated with MDD.8–10 In addition, the association between BDNF and geriatric depression has been suggested.11

BDNF arises from a precursor, proBDNF, which is proteolytically cleaved to produce the mature protein through the tissue-type plasminogen activator (tPA)–plasmin pathway, and represents one mechanism that can regulate the action of BDNF.12,13 Plasminogen activator inhibitor-1 (PAI-1) concentration, which is the major inhibitor for tPA, was found to be higher in young women with MDD than in controls.14 Pawlak et al. observed that tPA -/- mice were protected from stress-induced decline of neuronal and cognitive functions in the mouse hippocampus, which was important for the pathogenesis of MDD.15 The result indirectly supported that tPA was related with MDD. Tsai first proposed that the tPA–plasminogen system may be implicated in the pathogenesis of MDD.16 Following studies found that depressed subjects had higher levels of PAI-1 activity and that statins could act through the tPA–plasminogen pathway to increase BDNF and achieve an antidepressant effect.17,18

In the present study we investigated whether the plasma BDNF/tPA levels in untreated patients with late-onset geriatric depression (LGD) would be altered from healthy controls or whether antidepressant treatment can change the plasma levels of BDNF/tPA levels in LGD. The aim was to further explore the special meaning of the changes of BDNF/tPA levels in LGD.

METHODS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENT
  7. REFERENCES

Subjects and clinical assessment

The study design was reviewed by an appropriate ethics committee of Nanjing Medical University. All subjects provided written informed consent. 24 study subjects, 9 men and 15 women aged >60 years (mean age, 69.21 ± 6.46 years) who met diagnostic criteria for MDD (DSM-IV Axis I)19 at an age >55 years, and 30 normal volunteer controls, 10 men and 20 women (mean age, 70.00 ± 6.19 years) entered the study between December 2005 and June 2007. All participants were evaluated by the senior psychiatrist (Yuan Y) at the Affiliated Brain Hospital of Nanjing Medical University.

None of the patients had a history of other major psychiatric illness, including substance abuse or dependence or other primary neurological illness, including dementia or stroke. All study subjects did not receive any statins or have any other syndrome that may correlate to tPA levels such as diabetes or nephropathy.20,21 Patients who smoked were also excluded.22

The severity of depression was assessed by trained raters using the Hamilton Depression Rating Scale (HDRS).23 The patients' baseline HDRS scores >17. Healthy controls were enrolled from the general community and were free of a history of any DSM-IV Axis I or II disorder, major physical illness, alcohol or drug abuse and dependence. The healthy controls had HDRS scores <7. Age and gender were matched between LGD patients and healthy control subjects.

Efficacy assessment

Clinical response to selective serotonin re-uptake inhibitors (SSRI) was considered when a decrease of at least 50% in the baseline HDRS scores occurred. Remission criteria were HDRS scores ≤7 by the end of 6 weeks of treatment.24

Plasma BDNF and tPA

Before the initiation of therapy the patient had to be off all antidepressant medications for at least 2 weeks, to minimize the chance that discontinuation symptoms might be misinterpreted as depressive symptoms or medication adverse effects. After completion of the washout, plasma samples from the patients and healthy controls were collected between 06.00 and 08.00 hours and stored at −70°C until used for assay. All the subjects were required to complete the HDRS assessment on the day of plasma sample collection. The following antidepressant drugs were administered to the 24 patients who completed the HDRS assessments and the plasma sample collections after 6 weeks of treatment: nine patients received fluoxetine at a mean dose of 32 mg/day, nine patients received paroxetine at a mean dose of 38 mg/day, and six patients received 100 mg/day of sertraline. After the end of antidepressant treatment, the plasma sample and the HDRS assessment were completed again for comparison with baseline.

The concentrations of plasma tPA were measured using enzyme-linked immunosorbent assay (ELISA; Sun Biomedical, Shanghai, China). Plasma BDNF levels were measured within 1 month on ELISA using the Human BDNF ELISA Kit (EK0307; Boster Biomedical, Wuhan, China). All samples were tested in duplicate and the mean was calculated. The intra- and inter-assay coefficients of variation were <5% and <7%, respectively. If the variation of two results was >5%, the samples were retested and the mean taken for analysis.

Statistical analysis

The data are expressed as mean ± SD and were analyzed using SPSS version 10.0 (SPSS, Chicago, IL, USA). Chi-squared analysis was performed on categorical data, such as gender, and study groups were compared for continuous variables using paired t-test and anova. The relationships between the plasma tPA and/or BDNF and clinical variables were examined using Pearson's correlation coefficient. Statistical significance was set at P < 0.05.

RESULTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENT
  7. REFERENCES

There were no significant differences in age, gender, education and body mass index (BMI) between LGD patients and healthy controls (all P > 0.05; Table 1).

Table 1.  Subject characteristics
 Patients (n = 24)Controls (n = 30)P
  1. BMI, body mass index; HDRS, Hamilton Depression Rating Scale.

Age (years)69.21 ± 6.4670.00 ± 6.190.649
Sex (M/F)9/1510/200.283
Education (years)7.38 ± 4.576.54 ± 4.170.981
Age at onset (years)64.88 ± 7.13  
Duration of illness (years)4.45 ± 4.96  
Episodes3.29 ± 2.36  
BMI (kg/m2)21.42 ± 3.120.23 ± 2.020.153
HDRS28.63 ± 6.782.73 ± 1.480.000

At baseline, the HDRS scores in LGD patients (28.63 ± 6.76) were higher than healthy controls (2.73 ± 1.48, P = 0.00). The concentrations of plasma BDNF (859.83 ± 211.36 pg/mL) and tPA (6.623 ± 2.65 ng/mL) were significantly lower in the patients compared with healthy controls (BDNF: 958.83 ± 150.20 pg/mL, P = 0.037; tPA: 12.53 ± 5.35 ng/mL, P = 0.000).

For the whole group, the response rate was 0.46; the remission rate was 0.33. The individual HDRS score changes are given in Fig. 1. The HDRS score (11.75 ± 6.81) was significantly lower in the post-treatment than the pre-treatment group (P = 0.00), but it was still significantly higher than healthy controls (Fig. 2a). After 6 weeks' treatment the level of plasma BDNF (906.94 ± 145.44 pg/mL) was higher than baseline but the difference was not statistically significant. Furthermore, there were no significant differences in plasma BDNF level between before and after treatment, in either the responder or non-responder groups (Fig. 2b,c). The mean plasma BDNF level was not significantly different between the post-treatment group and healthy controls (P = 0.269). For the plasma tPA level there was no difference between the pre-treatment (6.623 ± 2.65 ng/mL) and post-treatment groups (5.88 ± 2.47 ng/mL). The post-treatment group still had significantly lower levels than healthy controls (P = 0.00; Fig. 2d).

image

Figure 1. Changes in Hamilton Depression Rating Scale (HDRS) total score before and after 6 weeks of treatment (—, responder; - - -, non-responder).

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image

Figure 2. Changes in (a) Hamilton Depression Rating Scale (HDRS) score, (b) plasma brain-derived neurotrophic factor (BDNF) and (d) tissue-type plasminogen activator (tPA) concentrations in late-onset geriatric depression (LGD) patients compared to healthy controls; and (c) plasma BDNF level in responders vs non-responders (inline image, before treatment; □, after treatment). *P < 0.05, **P < 0.01.

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No significant correlation was observed between plasma BDNF and tPA levels in LGD patients (r = −0.199, P > 0.05) or controls (r = 0.048, P > 0.05). Neither plasma BDNF levels nor tPA levels in LGD was significantly associated with HDRS scores. Moreover, there were no correlations among age, BMI, education, age of onset, episodes, duration of illness or plasma tPA levels as well as BDNF levels (P > 0.05).

DISCUSSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENT
  7. REFERENCES

The present findings indicated that lower plasma BDNF and tPA levels were important peripheral markers for patients with LGD. Several reports showed that patients with depressive episode had lower levels of BDNF plasma concentrations compared to healthy control.8–10 Many studies indicated that there was a relationship between serum BDNF levels and antidepressant treatment in depressive patients.25–27 The present results indicated a gradual normalization of plasma BDNF after 6 weeks of treatment with SSRI. Lee and Kim demonstrated that plasma BDNF levels increased significantly in depressive patients after antidepressant administration for 6 weeks in the responder group, but that there was no significant change in the non-responder group.28 These findings were partly consistent with the present results. The possible reasons were small sample size and the character of the present late-onset patients. In addition, Piccinni et al. reported that no significant difference was seen in the plasma BDNF levels between patients and healthy controls from 1 month to 1 year of antidepressant treatment.10 The present results are in agreement with these, suggesting that BDNF may be regarded as a peripheral marker for the action mechanism of antidepressant drugs.

To our knowledge, this is the first study addressing the role of tPA levels in LGD patients without cardiovascular disease (CVD), because tPA was thought to the bridge that connected MDD and CVD.29 As to the higher relationship between smoking and incidence of CVD, which could influence the tPA levels, we excluded patients who smoked.22 In the present study we found that there was a significant difference in plasma tPA level between pre-treatment LGD patients and healthy controls. Previous investigators have demonstrated that acute mental stress significantly reduced plasma tPA levels.30 Pietraszek et al. also reported that depression patients had significantly lower plasma tPA concentrations than healthy controls.31 These findings are consistent with the present study. After antidepressant treatment, tPA was still lower than before treatment but there was no significant difference. According to previous studies, only a small change was noted in plasma tPA levels, even after long-term treatment.32,33 This is the first study on the relationships of plasma tPA, LGD and SSRI. The effects of tPA on LGD and antidepressant treatment are unclear. PAI-1 is the major inhibitor for tPA, which was found to be related to MDD pathogenesis. A recent genetic study found that the PAI-1 gene SERPINE1 was associated with antidepressant treatment response.34 Therefore, for the present results, it is possible that the antidepressant might not affect the plasma tPA level directly.

Unfortunately we did not find a significant correlation between plasma BDNF, plasma tPA and HDRS score before antidepressant treatment in LGD patients. As to the plasma BDNF, the present results are consistent with the study by Kim et al.8 For plasma tPA, there was little direct evidence for the relationship with HDRS. Moreover, there was no significant correlation of tPA with BDNF. In future, we will enlarge and follow up the subjects for further research on the relationships between tPA, BDNF and HDRS.

Some limitations of the current study should be mentioned. First, it was carried out on a small number of patients and short-term follow up, replication with large samples and longitudinal follow up will be needed to overcome these limitations. In addition, we measured only plasma levels of BDNF and tPA. Not only tPA but also PAI-1 need to measured in future studies.

Conclusion

Baseline plasma BDNF and tPA levels were significantly lower in the LGD patients than healthy controls. After 6 weeks treatment with SSRI, plasma BDNF level tended towards a rise, but the plasma tPA was still lower than in healthy controls. As for the relationship between tPA, BDNF and HDRS, we found no significant difference in patients or healthy controls. This may imply, however, a non-linear relationship of tPA with BDNF. The finding further supports that neurotrophic systems may be involved in the etiology of MDD.

ACKNOWLEDGMENT

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENT
  7. REFERENCES

This study was supported by grants from Key Program of Medical Development of Nanjing (No: ZKX07018 Yonggui Yuan).

REFERENCES

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENT
  7. REFERENCES
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