Combining ECT with pharmacological treatment of depressed inpatients in a naturalistic study is not associated with serum BDNF level increase
Introduction
Brain-derived neurotrophic factor (BDNF) is the most extensively evaluated neurotrophin involved in mood disorders (Krishnan and Nestler, 2010). Many studies, including meta-analyses, have shown that BDNF blood levels are reduced in major depressive disorder (Huang and Lin, 2015, Krishnan and Nestler, 2008, Brunoni et al., 2008, Sen et al., 2008, Dwivedi, 2009, Molendijk et al., 2014) and that the BDNF receptor tropomyosin-related kinase B (TrkB) is increased in this disorder (Hung et al., 2010). The most commonly studied polymorphism of BDNF is Val66Met (rs6265), and previous studies have associated this polymorphism with early antidepressant response (Xu et al., 2012) and remission (Taylor et al., 2010).
There is evidence that pharmacological antidepressant treatment can increase BDNF levels in patients suffering from major depressive disorder (Huang et al., 2008, Sen et al., 2008, Guilloux et al., 2012, Wolkowitz et al., 2011, Matrisciano et al., 2009, Serra-Millàs et al., 2011). Additionally, studies also suggest an increase in serum and plasma BDNF after electroconvulsive therapy — ECT (Bocchio-Chiavetto et al., 2006, Marano et al., 2007, Okamoto et al., 2008, Piccinni et al., 2009, Hu et al., 2010, Haghighi et al., 2013, Bilgen et al., 2014, Brunoni et al., 2014).
Although there is an association of both interventions (ECT and pharmacological) with BDNF levels, few studies evaluate the combined treatments. A previous published RCT compared a group of depressive patients only receiving pharmacological treatment — in this case citalopram — to another group receiving the drug as well as ECT (combined group). Plasma BDNF increased in both groups over time, with higher plasma BDNF levels in the combined group (Haghighi et al., 2013).
Few studies have evaluated the association between BDNF levels and ECT in clinical contexts where there was a response following treatment. Okamoto et al. (2008) showed that serum BDNF levels increased significantly in responders to ECT, whereas in non-responders these levels remained unchanged. Other studies had reported negative findings for the correlation between variations in depressive symptoms and BDNF levels (Fernandes et al., 2009, Haghighi et al., 2013).
Although RCTs are the gold standard model for medical studies, often their capacity for generalization is limited in clinical practice, especially in relation to treatment models with particularities such as ECT. Naturalistic studies have the advantage of better representing the 'real world', but the naturalistic design has limitations such as lack of randomization. The results of these two models complement each other. Regarding BDNF analysis in ECT, most previous studies are RCTs; therefore, it is interesting to replicate previous results using a naturalistic study design.
The objectives of this study are (1) to determine if antidepressant treatments (either an exclusive pharmacologic treatment or a pharmacologic treatment combined with ECT) could affect BDNF levels in a naturalistic study; (2) to investigate if combining ECT with pharmacological treatment affects BDNF levels differently from exclusively pharmacological treatment; (3) compare BDNF levels of these two groups before and after treatment with one measure of BDNF from normal controls; and (4) to investigate changes in BDNF levels in depressive subjects with clinical response to treatment. Our hypotheses are (1) both groups would show an increase in BDNF levels; (2) combining ECT with pharmacological treatment would result in higher BDNF levels compared with pharmacological treatment alone; (3) the BDNF levels of the combined group would be restored to the levels of healthy controls; and (4) BDNF increases would also be present in responders to both treatments.
Section snippets
Methods
The methodology involved in this study is a naturalistic prospective cohort study analyzing the effects of combining ECT with pharmacological treatment on BDNF levels of depressed inpatients, with a comparison to a healthy control group at discharge.
This study is part of a larger prospective cohort study called “Evaluation and follow-up of patients with severe mental illness: diagnostic factors, prognosis and treatment and its association with biological markers.”
The Ethical and Scientific
Results
There were no significant differences between losses and included subjects in terms of HDRS-17 at admission, age or sex, confirming that losses were not subject to bias (Table 1).
Table 2 presents epidemiologic and clinical variables — including the medication used during treatment — of the treatment groups and comparisons between them. A significant difference was found for gender (a significantly higher proportion of women in the combined group), use of selective serotonin reuptake inhibitor
Discussion
Our naturalistic study found that the combination of ECT with pharmacological treatment was not associated with an increased serum BDNF level. We also found no difference in BDNF levels between admission and discharge either in the pharmacological group or the combined group. Neither group reached the levels of healthy controls.
In an RCT design study, Haghighi et al. (2013) compared plasma BDNF levels between a group of depressive patients receiving only 40 mg/day citalopram (control group) and
Conclusion
In this naturalistic study, there was no difference in terms of serum BDNF levels when ECT was combined with pharmacological treatment and no differences between admission and discharge in the pharmacological-only group or in the combined treatment group. Significant differences in serum BDNF were not found in treatment responders. The BDNF levels of depressive inpatients at admission and at discharge were lower than in healthy controls.
More naturalistic works are needed to study biological
Contributors
Thiago Fernando Vasconcelos Freire participated in the preparation of the research project, in data collection, in statistical analysis and in preparation of the article. Marcelo Pio de Almeida Fleck and Neusa Sica da Rocha developed and coordinated the research project, submitted the project to the Research Ethics Committee, oversaw data collection, participated in the statistical analysis and in the preparation of the article. All authors have approved the final article.
Funding source
−This study was financially supported by CAPES (Coordenação de Aperfeiçoamento Profissional de Nível Superior), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico), FIPE/HCPA (Fundo de Incentivo à Pesquisa e Eventos do Hospital de Clínicas de Porto Alegre) and FAPERGS (Fundo de Amparo à Pesquisa do Estado do Rio Grande do Sul).
Conflicts of interest
The authors declare that they have no conflict of interest.
Acknowledgments
We thank the Molecular Psychiatry Laboratory of the Hospital de Clínicas de Porto Alegre for his molecular analyses. We also thank the psychiatric inpatient unit of the Hospital de Clínicas de Porto Alegre. We are grateful to the Grupo de Pesquisa e Pós-Graduação (GPPG) of the Hospital de Clínicas de Porto Alegre for the statistical analyses and funding of this study. We thank CAPES (Coordenação de Aperfeiçoamento Profissional de Nível Superior), CNPq (Conselho Nacional de Desenvolvimento
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