Electroconvulsive therapy (ECT) is effective in treatment-resistant depression (TRD). It may act through intracellular process modulation, but its exact mechanism is still unknown. Animal research supports a neurotrophic effect for ECT. We aimed to investigate the association between changes in serum brain-derived neurotrophic factor (sBDNF) levels and clinical improvement following ECT in patients with TRD. Twenty-one patients with TRD (2 men, 19 women; mean age, 63.5 years; S.D., 11.9) were assessed through the Hamilton Depression Rating Scale (HDRS), the Brief Psychiatric Rating Scale (BPRS), and the Clinical Global Impressions scale, Severity (CGIs) before and after a complete ECT cycle. At the same time-points, patients underwent blood withdrawal for measuring sBDNF levels. ECT significantly reduced HDRS, BPRS, and CGIS scores, but not sBDNF levels. No significant correlation was found between sBDNF changes, and each of HDRS, BPRS, and CGIs score changes. sBDNF levels in TRD patients were low both at baseline and post-ECT. Our results do not support that improvements in TRD following ECT are mediated through increases in sBDNF levels.
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 and 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 and 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 and 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 and 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 and Aydemir et al., 2005; Huang et al., 2005; 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 and 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 and Haghighi et al., 2013), while others have reported no change after ECT (Fernandes et al., 2009, Grønli et al., 2009 and 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.
