Electroconvulsive therapy (ECT) and aerobic exercise training (AET) increased plasma BDNF and ameliorated depressive symptoms in patients suffering from major depressive disorder

https://doi.org/10.1016/j.jpsychires.2016.01.012Get rights and content

Highlights

  • Patients with treatment-resistant MDD were investigated.

  • Treatment: ECT, aerobe exercise training (AET), or ECT + AET.

  • Depression decreased and plasma BDNF increased in all study conditions.

  • Greatest decrease of depression with ECT + AET; Highest increase of plasma BDNF with ECT.

  • Plasma BDNF levels were not associated with symptoms of depression.

Abstract

Background

To treat patients suffering from major depressive disorder (MDD), research has focused on electroconvulsive therapy (ECT) and aerobic exercise training (AET). Brain derived neurotrophic factor (BDNF) seems to be key in MDD. The aims of the present study were therefore two-fold, to investigate in a three-arm interventional study the differential effects of ECT, ECT plus AET, and AET alone in patients suffering from TR-MDD on 1. depressive symptoms and 2. plasma BDNF (pBDNF).

Methods

60 patients with MDD (mean age: 31 years; 31.6% female patients) were randomly assigned either to the ECT, ECT + AET, or AET condition. The AET condition consisted of treadmill exercise for 45 min, three times a week. Both depression severity and pBDNF levels were assessed at baseline and 4 weeks later. All patients were further treated with an SSRI standard medication.

Results

pBDNF levels increased over time in all three study conditions, though, highest increase was observed in the ECT + EAT condition, and lowest increase was observed in the AET condition. Depressive symptoms decreased in all three conditions over time, though, strongest decrease was observed in the ECT + AET condition. The combination of ECT + AET led to significantly greater remission rates than in either the ECT or AET alone conditions. BDNF levels were not associated with symptoms of depression.

Conclusions

The pattern of results suggests that ECT, AET and particularly their combination are promising directions for the treatment of patients suffering from MDD, and that it remains unclear to what extent pBDNF is key and a reliable biomarker for MDD.

Introduction

In a previous paper (Salehi et al., 2014), due to a misunderstanding in the data transfer, we published by mistake data belonging to another study. Accordingly, the previous publication has been retracted (Salehi et al., 2015). In the present manuscript, the statistical computations were performed with the correct data set. The German Editorial Office of the Journal of Psychiatric Research has got the correct SPSS-file, and this office is able to check the data. We underscore that the pattern of results reported in the previous and retracted paper (Salehi et al., 2014) remained unchanged. Besides the correct data, we took advantage of the situation to update the Introduction section as regards more recent findings of the influence of physical activity as add-on in the treatment of patients with diagnosed major depressive disorders.

Major depressive disorders (MDD) are among the most prevalent lifetime psychiatric disorders, and Murray and Lopez (1997) estimated that MDD will be the third leading cause of burden worldwide by 2020, further associated with chronic lifelong risk for recurrent relapse, and high morbidity, co-morbidity and mortality (Lockwood et al., 2015). Further, residual depressive symptoms are associated with poor long-term outcomes and increased risk of relapse (Fava et al., 2002, Judd et al., 1998, Kennedy and Paykel, 2004). Accordingly, adequate treatment and care of patients suffering from MDD is highly desirable from both clinical and economic points of view. To address this issue, we investigated the impact of a 4-week electroconvulsive therapy (ECT) and aerobic exercise training (AET) in patients with MDD.

Research on possible molecular pathways of MDD has shown that increased cellular dysfunction in limbic and cortical areas of the brain can be observed in patients suffering from MDD (cf. Guilloux et al., 2012, Sen et al., 2008), and it is strongly related to decreased neurotrophic activity (Duman and Monteggia, 2006). In this regard, the search for biomarkers, including nerve growth factors such as brain-derived neurotrophic factor (BDNF), that reliably predict and describe improvements in treatment of depressive disorders has become an increasingly important focus of research (Naert et al., 2011, Mikoteit et al., 2014). BDNF is a protein mostly expressed in the central nervous system and has an importance in survival and maintenance of neuronal functioning (Binder and Scharfman, 2004). Indeed, low neurotrophic activity has been seen as a mechanism underlying reduced cell numbers in the frontal cortex (Cotter et al., 2001, Rajkowska et al., 2001), and the amygdala (Bowley et al., 2002, Hamidi et al., 2004) and also underlying hippocampal volume (Videbech and Ravnkilde, 2004, Campbell et al., 2004), thus indicating that nerve growth factors, and more specifically, changes in BDNF, may play a crucial role in the development of and recovery from MDD (Castrén et al., 2007, Karege et al., 2002, Sen et al., 2008, Molendijk et al., 2011, Sen et al., 2008, Guilloux et al., 2012, Wolkowitz et al., 2011, Matrisciano et al., 2009, Serra-Millàs et al., 2011, Mikoteit et al., 2014). In this context, Guilloux et al. (2012) were able to show reduced BDNF function in the amygdala of females suffering from MDD. Likewise, Sen et al. (2008) concluded from a meta-analysis that BDNF-levels were lower in people suffering from MDD than in controls. Following Hasselbalch et al. (2012) this holds also true even when patients are fully remitted. However, as a result, it is claimed that, among other factors, increasing the levels of plasma BDNF might be associated with improvements in MDD (cf. Siuciak et al., 1997, Shirayama et al., 2002).

There is a large body of evidence that electroconvulsive therapy (ECT, Haghighi et al., 2013) and aerobic exercise training (AET) both improve depressive symptoms (Josefsson et al., 2014, Lindwall et al., 2014, Mura et al., 2014, Vancampfort et al., 2015, Rosenbaum et al., 2014) and boost secretion and the effect of BDNF (Cho et al., 2012, Seifert et al., 2010, Brunoni et al., 2014). Therefore, the aim of the present study was to investigate the impact of ECT and AET concomitantly on depressive symptoms and BDNF in patients suffering from MDD.

As to the impact of ECT on BDNF-levels when treating MDD, in an attempt to summarize the state of play, Haghighi et al. (2013), in a very brief review on the topic, reached the following conclusions: (1) in sample sizes ranging from 15 to 40 in-patients suffering from MDD, during a depressed episode of unipolar or bipolar disorder, BDNF increased exclusively in plasma (pBPNF), but not in serum BDNF (sBDNF) in response to ECT applied either bifrontal, unilateral, or bilateral; (2) two or three sessions per week were performed, (3) lasting for 2.5–5 weeks; (4) patients were assessed with concomitant antidepressants (SSRIs, NASSAs, trizyclic antidepressants), antipsychotics, or benzodiazepines, or during the wash-out phase; and (5) in most studies, the association between change in BDNF and psychopathology remained unclear. To conclude, given the heterogeneity with respect to the factors mentioned above, the mixed results are not surprising (see also Scott et al., 2000). In a previous study (Haghighi et al., 2013), we showed that sBDNF levels increased by 101% in patients with treatment-resistant MDD, compared to sBDNF levels of patients with treatment-resistant MDD treated with a citalopram, though the increase in sBDNF was not associated with increased symptom reduction or with treatment outcome. The latter observation is in accord with a recent meta-analysis and review in this field: Specifically, Brunoni et al. (2014), analyzing 11 different ECT studies covering 221 subjects suffering from mood disorders during an acute phase of depressive episode, concluded that (1) different algorithms (unilateral vs. bilateral), (2) different topographic placements (e.g. frontal vs. temporal), (3) a different number of trials, while (4) assessing plasma or serum BDNF were employed. However, two robust key results could be observed: First, regardless of the differences mentioned above, ECT did markedly improve levels of BDNF; second, BDNF levels and depressive symptoms were not associated; accordingly, Brunoni et al. (2014) concluded that this lack of correlation between BDNF increasing and depression improvement seemed to reflect that ECT induces neurotrophic effects regardless of clinical response in depression.

Aerobic exercise training has a positive impact on patients suffering from burnout (Beck et al., 2013), on cardiorespiratory fitness (Gerber et al., 2013, Lindwall et al., 2014), and on depression, stress and burnout (Lindwall et al., 2014). Most importantly, Mota-Pereira et al. (2011) showed, that compared to the control condition, 50% of female patients suffering from TR-MDD were remitted after a 12-week walking AET. In brief, there is evidence that AET has a beneficial impact on patients suffering from a broad variety of psychiatric disorders (see also Josefsson et al., 2014, Rethorst and Trivedi, 2013), and more specifically on patients suffering from affective disorders (Stanton et al., 2014).

Aerobic exercise training (AET) increases sBDNF, pBDNF and platelet BDNF (Cho et 2012). Of particular note, Seifert et al. (2010) showed that brain BDNF increased in seven healthy males after 3-months with AET, compared to five healthy males in a sedentary condition.

To the best of our knowledge, only one study has examined the association between BDNF and AET in patients suffering from MDD. Toups et al. (2011) assessed 104 patients suffering from MDD and found no association between BDNF and the efficacy of an exercise augmentation treatment.

To summarize, MDD dramatically reduces individuals’ quality of life and increases costs and burden for public expenditure. Both ECT and AET have the potential to successfully treat patients suffering from MDD, and a key factor seems to be the release of circulating BDNF. However, surprisingly, no study has so far considered to the extent of positive impact of the combination of ECT and AET on both circulating BDNF and symptoms of depression. The aims of the present study were therefore two-fold: to investigate in a three-arm interventional study the differential effects of ECT alone, ECT with AET, and AET alone in patients suffering from MDD on (1) depressive symptoms, and (2) BDNF concentrations. We believe the results have the potential to optimize treatment of patients suffering from MDD.

Three hypotheses and one research question were formulated. First, following Haghighi et al. (2013) and Brunoni et al. (2014), we expected that ECT would improve both symptoms and pBDNF in patients suffering from MDD. Second, following Mota-Pereira et al. (2011) and others, we hypothesized that AET would improve symptoms in patients suffering from MDD. Third, following Seifert et al. (2010) and others, we expected increased pBDNF levels following AET. Last, we treated as exploratory the extent to which the combination of ECT and AET has additive effects. To the extent that it does we would expect greater symptom improvement and higher pBDNF levels among MDD patients following ECT in combination with AET.

Section snippets

Sample

A total of 70 inpatients suffering from major depressive disorders (MDD) and meeting the inclusion and exclusion criteria as outlined below were approached and diagnosed according the Diagnostic and Statistical Manual of Mental Disorders - 4th edition, text revision (DSM-IV-TR) criteria (American Psychiatric Association, 2000). Of these, 60 patients (85.7%) agreed to participate in the study (mean age: M = 29.67, SD = 5.81; 30% females). Patients were fully informed about the study aims and

Correlative computations between demographic variables, pBDNF, and depressive symptoms

Table 2 gives the correlations between age, number of previous depressive episodes, BDI scores, HDRS and pBDNF values (always pre- and post-assessments). Age and the number of episodes were neither associated with pBDNF, nor with depressive symptoms (self- and experts' ratings). Depressive symptoms as assessed via self- and experts' ratings were positively correlated, but pBDNF values were not related to depressive symptoms (as assessed via self- and experts’ ratings).

pBDNF and depressive symptoms over time and between groups

Table 3 reports the

Discussion

The key findings of the present study are that among a large sample of patients suffering from major depressive disorder (MDD), electroconvulsive therapy (ECT), aerobic exercise training (AET), and the combination of ECT and AET all led to significant symptom improvements, both as rated by patients and by experts. Further, the highest remission rate was found in the ECT + AET condition. Concomitantly, pBDNF levels increased in all three study conditions, but pBDNF and symptom improvements were

Conclusions

Among a sample of patients suffering from major depressive disorder (MDD), ECT and aerobic exercise training (AET) led to symptom improvements and an increase in pBDNF. Most importantly, the combination of ECT and AET led to the greatest symptom improvements and highest pBDNF levels. However, pBDNF and depressive symptoms were not associated. We conclude that pBDNF is not a suitable biomarker in patients suffering from MDD.

Contributors

IS, SMH, MH, LJ, HB, MG, UP, RK, EHT and SB designed the study and wrote the protocol, and all of them managed the literature searches and analyses. IS, SMH, MH, and LJ were highly engaged with data collection and data entry. SB undertook the statistical analyses, and MG and RK the statistical check. SB wrote the draft of the manuscript and coordinated the integration of the different comments and corrections of the authors. All authors contributed to and have approved the final manuscript.

Role of funding

The present study was not financially supported by any kind of external funding.

Financial disclosure

All authors declare no conflicts of interest. The entire study was conducted without external financial support.

Acknowledgments

We thank Nick Emler (University of Surrey, UK) for proofreading the manuscript.

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