Electroconvulsive therapy improves clinical manifestations of treatment-resistant depression without changing serum BDNF levels
Introduction
Treatment-resistant depression (TRD) is highly disabling, with about 50% of patients experiencing a chronic course and 20% showing insufficient response in spite of aggressive pharmacological and psychotherapeutic interventions (Fava et al., 2003, Hussain and Cochrane, 2004). Electroconvulsive therapy (ECT) is one of the most effective treatments for treatment-resistant depression, with a remission rate of 70–90%, which is higher than that of standard antidepressant treatment (Berton and Nestler, 2006). Despite clinical efficacy, its molecular mechanism of action remains unclear. Understanding the biological mechanisms underlying effective antidepressant treatments may contribute to the identification of therapeutic response biomarkers and to the improvement of current treatments. Different parameters such as cortisol, adrenocorticotropic hormone, corticotrophin-releasing factor, thyroid-releasing hormone, thyroid-stimulating hormone, prolactin, oxytocin, vasopressin, dehydroepiandrosterone sulfate, and tumor necrosis factor α, have been proposed as potential biomarkers of the effect of ECT (Wahlund and von Rosen, 2003, Hestad et al., 2003). However, animal and human data have been heretofore inconsistent, hence, no ECT biomarker is routinely used in clinical practice.
Accumulating evidence from animal studies supports a neurotrophic effect of ECT. Pre-clinical studies have shown that electroconvulsive seizures lead to increased hippocampal neurogenesis (Scott et al., 2000) and angiogenesis (Newton et al., 2006), and enhanced glial proliferation in frontal cortex (Ongür et al., 2007).
Over the past decades, different studies suggested that brain-derived neurotrophic factor (BDNF) might be involved in the pathophysiology of mood disorders. BDNF is a member of the nerve growth factor family, recognized to mediate cell growth, synaptic connectivity, and neuronal repair and survival (Laske and Eschweiler, 2006). BDNF abounds in the brain and peripheral tissues. It is mainly stored in human platelets; its serum levels are 100-fold higher than its plasma levels (Yamamoto and Gurney, 1990). This difference is due to platelet degranulation during clotting (Fujimura et al., 2002). However, there are other potential cellular sources of plasma BDNF, including vascular endothelium, smooth muscle cells, activated macrophages, and lymphocytes, and since BDNF readily crosses the blood–brain barrier, it is likely that some of serum BDNF (sBDNF) may be of brain origin (Lommatzsch et al., 2005). BDNF has been hypothesized to play a role in depressive behavior and suicide (Brent et al., 2010, Taliaz et al., 2010, Taliaz et al., 2011). Studies have reported that blood (serum or plasma) BDNF levels are decreased in drug-free depressive patients (Karege et al., 2002, Shimizu et al., 2003, Fernandes et al., 2011), although higher levels were found in the most severely depressive subgroup of better antidepressant responders in one study (Mikoteit et al., 2014), witnessing the unpredictable nature of the association between BDNF changes and depressive psychopathology. sBDNF tends to increase with long-term antidepressant treatment (Shimizu et al., 2003, Aydemir et al., 2005, Huang et al., 2008, Molendijk et al., 2011). The mechanism by which increased BDNF expression could improve depression is unclear. Duman and colleagues have hypothesized that BDNF induces neuronal sprouting in brain regions like the hippocampus and cerebral cortex and improves synaptic connectivity and function of neural circuits involved in mood regulation (Duman et al., 1997, Duman and Vaidya, 1998). Electroconvulsive seizures increased BDNF gene expression and levels in various animal brain areas (Altar et al., 2003), but whether ECT affects blood BDNF levels in depressive patients remains controversial. Blood BDNF levels reflect brain concentrations across various species (Klein et al., 2011), hence it is appropriate to investigate sBDNF concentrations to infer about a treatment׳s effect on brain BDNF concentrations. Some studies have shown an increase in blood BDNF levels after ECT (Bocchio-Chiavetto et al., 2006, Marano et al., 2007, Okamoto et al., 2008, Hu et al., 2010, Haghighi et al., 2013), while others have reported no change after ECT (Fernandes et al., 2009, Grønli et al., 2009, Gedge et al., 2012). However, even if plasma (Haghighi et al., 2013) and serum (Salehi et al., 2014) levels were increased by ECT in two studies, the changes were unrelated to symptom improvement.
We aimed to investigate the association between changes in sBDNF levels and clinical improvement after ECT in patients with TRD.
Section snippets
Patients
We conducted a prospective study of 21 patients with treatment-resistant depressive episode (2 men and 19 women, mean age 63.5 years ±11.9 S.D.). Each patient was his/her own control. Patients were recruited at the Neuropsychiatry Department of Villa Rosa Hospital Viterbo, affiliated to Sapienza University, Rome, Italy, between September 2011 and December 2013. They met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR; American Psychiatric
Results
Socio-demographic data (age, gender, cigarette smoking, lifetime alcohol abuse, marital status, living status, education level) were collected from patients at recruitment and are shown in Table 1. HDRS scores dropped significantly in patients from 23.2±4.16 (mean±S.D.) at T0 to 8.52±1.72 at T1 (Table 2). CGIs and BPRS scores also dropped significantly from T0 to T1 (Table 2). Patients׳ T0 mean sBDNF levels did not differ statistically from T1 levels (11.8±2.81 ng/ml vs. 11.1±2.54 ng/ml,
Discussion
The main finding of this study was that changes in sBDNF levels did not correlate with changes in depression severity. Baseline sBDNF levels in our TRD sample were lower than commonly reported normal values (Lang et al., 2004), which matches previous data (Karege et al., 2002, Lee et al., 2007, Matrisciano et al., 2009, Wolkowitz et al., 2011), and supports the hypothesis of neurotrophic factor deficits in the pathogenesis of TRD (Sen et al., 2008). Some studies reported a negative correlation
Conclusions
This study provides evidence that ECT treatment is not associated with significant changes in BDNF levels in TRD and that changes do not correlate with the significant clinical improvement obtained with ECT. It is unlikely that sBDNF levels are somehow linked to the mechanisms of clinical amelioration of patients with TRD of various origins that benefit from ECT. Studies with a longer follow-up with parallel sBDNF-clinical status evaluations are needed to clarify whether sBDNF levels have a
Financial and competing interests disclosure
In the past 2 years, Paolo Girardi has received research support from Lilly, Janssen, and Springer Healthcare, and has participated in Advisory Boards for Lilly, Otsuka, Pfizer, Schering, and Springer Healthcare and received honoraria from Lilly and Springer Healthcare. All other authors of this paper have no relevant affiliations or financial involvement with any organization or entity with a financial interest in, or financial conflict with the subject matter or materials discussed in the
Acknowledgments
The authors wish to thank Ms Mimma Ariano, Ms Ales Casciaro, Ms Teresa Prioreschi, and Ms Susanna Rospo, Librarians of the Sant׳Andrea Hospital, School of Medicine and Psychology, Sapienza University, Rome, for rendering precious bibliographical material accessible, as well as their Secretary Lucilla Martinelli for her assistance during the writing of the manuscript.
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2020, Revista de Psiquiatria y Salud MentalCitation Excerpt :Despite a growing number of studies, findings on changes in BDNF levels and the response to ECT are controversial.18 A recent meta-analysis of 22 studies of BDNF blood levels after ECT in patients with major depressive disorder concluded that BDNF levels may increase after ECT, being a candidate to be used as an indicator of treatment response after one or more weeks of ECT.19 However, some studies reported that serum or plasma BDNF levels increase at different time points after ECT,20–29 while other research groups did not find any influence of ECT on BDNF levels.30–35 Recently, Sorri and collaborators reported a decrease of BDNF levels during the fifth ECT session, between the baseline and the 2-h samples, with no association between serum or plasma BDNF levels and remission.10
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