Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎

Contents lists available at ScienceDirect

Psychiatry Research journal homepage: www.elsevier.com/locate/psychres

Electroconvulsive therapy improves clinical manifestations of treatment-resistant depression without changing serum BDNF levels Chiara Rapinesi a,b, Georgios D. Kotzalidis a,n, Martina Curto a,c,d, Daniele Serata a,b, Vittoria R. Ferri a,b, Paola Scatena a,b, Paolo Carbonetti b, Flavia Napoletano a, Jessica Miele e, Sergio Scaccianoce e, Antonio Del Casale a,f, Ferdinando Nicoletti a,e, Gloria Angeletti a, Paolo Girardi a,b a NESMOS Department (Neurosciences, Mental Health, and Sensory Organs), Sapienza University of Rome, School of Medicine and Psychology, Sant'Andrea Hospital, Rome, Italy b Neuropsychiatry Department, Villa Rosa, Suore Hospitaliere of the Sacred Heart of Jesus, Viterbo, Italy c Department of Psychiatry, Harvard Medical School, Boston, MA, USA d Bipolar & Psychotic Disorders Program, McLean Hospital, Belmont, MA, USA e Department of Physiology and Pharmacology, Sapienza University, Rome, Italy f Department of Psychiatric Rehabilitation, Fondazione Padre Alberto Mileno Onlus, Vasto, Chieti, Italy

art ic l e i nf o

a b s t r a c t

Article history: Received 10 August 2014 Received in revised form 30 January 2015 Accepted 5 April 2015

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 brainderived 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. & 2015 Elsevier Ireland Ltd. All rights reserved.

Keywords: Electroconvulsive therapy (ECT) Brain-derived neurotrophic factor (BDNF), serum levels Treatment-resistant depression Major depression Bipolar depression

1. 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,

n

Corresponding author. Tel.: þ 39 0633775951; fax: þ 39 0633775342. E-mail address: [email protected] (G.D. Kotzalidis).

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 brainderived 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,

http://dx.doi.org/10.1016/j.psychres.2015.04.009 0165-1781/& 2015 Elsevier Ireland Ltd. All rights reserved.

Please cite this article as: Rapinesi, C., et al., Electroconvulsive therapy improves clinical manifestations of treatment-resistant depression without changing serum BDNF levels. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.04.009i

C. Rapinesi et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎

2

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, 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.

2. Materials and methods 2.1. Patients We conducted a prospective study of 21 patients with treatment-resistant depressive episode (2 men and 19 women, mean age 63.5 years 711.9 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 Association, 2000) diagnostic criteria for major depressive episode (MDE) with or without psychotic features. Diagnosis, duration of illness, presence of psychiatric comorbidities, and number of ECT sessions are specified in Table 1, along with sociodemographic data. ECT sessions were scheduled three times in a week, on alternate days. ECT treatment cycles were completed on the basis of treating physicians' clinical judgment. Psychotropic medications, including antidepressants, antipsychotics and mood stabilizers (amitriptyline 100–150 mg/ day in four cases, clomipramine 300 mg/day in three cases, sertraline 200 mg/day in three cases, fluoxetine 20–80 mg/day in five cases, fluvoxamine 300 mg/day in one case, citalopram 20–40 mg in two cases, venlafaxine 150–225 mg/day in three cases, olanzapine 5–10 mg/day in three cases, risperidone 3–4 mg/day in two cases, quetiapine 200–300 mg/day in two cases, lithium 900 mg/day in two cases, and valproate 1200 mg/day in four cases; more than one drug might refer to the same patient; all patients were receiving their medication regimen for at least 2 months), were discontinued before starting ECT and were suspended until the end of the ECT cycle. During the course of treatment, psychiatrists had the option of adding anxiolytic or sedative hypnotic medications for brief periods, based on clinical

Table 1 Sociodemographic and clinical and characteristics of our ECT TRD sample (N ¼21). Age (mean 7S.D.)

63.5 7 11.9

Gender (% Males) Cigarette smoking (%) Lifetime alcohol abuse (%) Marital status (%) Single Married Separated/divorced Widowed Living Status (n, %) Home alone Home with family Education (n, %) Primary school Secondary school High school Graduate school Diagnosis (%) Major depressive disorder, without psychotic symptoms Major depressive disorder, with psychotic symptoms Bipolar disorder Schizoaffective disorder Psychosis not otherwise specified Duration of illness (years) (mean 7S.D.) Psychiatric comorbidities (%) ECT sessions N (%) Six Nine 12

9.5 31.8 19.0 19.0 57.1 14.3 9.5 28.6 71.4 28.6 42.9 19.0 9.5 23.8 23.8 28.6 9.5 14.3 2.2470.89 23.8 N ¼14 (66.67) N ¼5 (23.81) N ¼2 (9.52)

Abbreviations: ECT, electroconvulsive therapy; S.D., standard deviation; TRD, treatment-resistant depression. necessity. Blood samples for BDNF assays were obtained at baseline, prior to their first ECT session (T0), and after having completed their ECT cycle (T1). Patients were fully informed about all therapeutic procedures and gave free, written consent for each treatment, and specifically for ECT. The study has been approved by the local ethical committee (Villa Rosa Hospital).

2.2. Clinical assessment We used the 21-item Hamilton Depression Rating Scale (HDRS) (Hamilton, 1960) to rate depression, the 18-item Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham, 1962; Overall, 1974) to rate general psychopathology, and the Clinical Global Impressions Severity of Illness (CGIs) scale (Guy, 1976) to rate overall clinical severity at T0 and T1. All three are clinician-rated scales; the first consists in a thorough interview investigating somatic and psychological symptoms of depression, whereas the third is a one-item Likert scale ranging from 1 (not at all ill) to 7 (extremely ill). Each BPRS item is also rated on a similar 1–7 Likert scale, where 1 is not present and 7 extremely severe. Certified clinicians rated both HDRS and BPRS, showing a high interrater reliability (Cohen's J¼ 0.89). Criteria for response and remission were an at least 50% drop of HDRS scores from T0 to T1, and a maximum score of 7 on the HDRS at T1.

2.3. ECT treatment Before receiving ECT, they were taken full medical and psychiatric history and status, and underwent physical examination along with routine blood chemistry, cardiovascular, dental, and neurological assessments to exclude any clinical contraindications. Electroconvulsive therapy was performed using a constant current Thymatron System IV brief-pulse ECT device (Somatics LLC, Lake Bluff, IL), delivering pulsed, bidirectional, brief, square-wave stimuli. Electrode placement was bilateral and bitemporal. The initial stimulus dosage was adjusted with the age method for all patients (Swartz and Abrams, 1996). The mean charge for the short-term course was from 302.4 to 504.0 mC, and the mean seizure length was from 30 to 100 s. Anesthesia was induced through intravenous midazolam, 6 to 18 mg, and muscle relaxation through intravenous succinylcholine, 60–100 mg. We monitored seizure activity both clinically and through bifrontal electroencephalography; the latter was used to ascertain seizure length. The patients were ventilated with 100% oxygen until resumption of spontaneous respiration. Physiological monitoring included pulse oximetry, blood pressure, electrocardiogram, and 1-channel electroencephalogram.

Please cite this article as: Rapinesi, C., et al., Electroconvulsive therapy improves clinical manifestations of treatment-resistant depression without changing serum BDNF levels. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.04.009i

C. Rapinesi et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎ The criterion for an adequate generalized seizure duration was at least 20 s of motor response and 25 s of electroencephalogram seizure activity. All patients experienced adequate seizures at their first ECT sessions. At subsequent sessions, current dosage was adjusted upward to maintain adequate seizure duration. Cycles could be considered completed after six, nine or 12 ECT sessions, according to clinician's judgment. 2.4. Blood collection and BDNF sample Blood samples to measure sBDNF levels were obtained from each participant between 10 a.m. and 12 a.m. and stored at  20 1C. Venous blood samples were obtained at T0 and T1. Five milliliter of blood were sampled in anticoagulant-free tubes and kept at room temperature for 1 h before serum isolation (centrifugation at 2000 rounds  10 min at 20 1C). sBDNF levels were measured through enzymelinked immunosorbent assay (ELISA) using a commercially available kit (BDNF Emax Immunoassay System, Promega, Italy). Ninety-six-well plates were coated with anti-BDNF monoclonal antibodies and incubated at 4 1C for 18 h. Plates were incubated in a blocking buffer for 1 h at room temperature to reduce nonspecific binding of sample and assay components in wells. Samples and BDNF standards were shaken at room temperature for 2 h, followed by washing with the appropriate washing buffer. The plates were incubated with anti-human BDNF polyclonal antibodies at room temperature for 2 h, extensively washed, and incubated with anti-IgY antibody conjugated to horseradish peroxidase for 1 h at room temperature. The plates were incubated in peroxidase substrate and tetramethylbenzidine solution to produce a color reaction. The reaction was stopped with HCl (1.0 M); optical density of each well was measured at 450 nm using an Emax plate reader. All samples were assayed in duplicate. Samples were analyzed 12 months after collection. Intra- and inter-assay coefficients of variability were 6.1% and 8.6%, respectively. 2.5. Statistical analysis SPSS version 19.00 (IBM Corporation, Armonk NY, USA) was used for data analysis. Continuous variables were expressed as mean 7standard deviation (S.D.), while discrete variables were assigned as numbers and percentages. The compliance of continuous variables with normal distribution was controlled with the Kolmogorov–Smirnov test. Whether pre- or post-ECT groups differed in terms of discrete variables was checked through Pearson's Chi Squared test (χ2). Since continuous variables did not comply with a normal distribution, the Mann– Whitney U test was used for intergroup comparisons. We used the Wilcoxon signed-rank test to compare dependent groups (measurements) and Spearman's Rho correlation (ρ) to test between-variable relationships. We set statistical significance at P o0.05.

3. 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 23.274.16 (mean7S.D.) at T0 to 8.5271.72 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 (11.872.81 ng/ml vs. 11.172.54 ng/ml, respectively, P¼0.131) (Table 2). T0 and T1 sBDNF levels did not significantly correlate with socio-demographic parameters (age, gender, cigarette smoking, alcohol abuse); however, while this was true also for T0 sBDNF levels and clinical scales (HDRS, BPRS, and CGIs), at T1 there was a curious

correlation between sBDNF and depressive scores on the HDRS, and also a trend between sBDNF and levels of psychopathology on the BPRS (Table 3). Patients' sBDNF did not change significantly post-ECT (Z¼  1.51; P¼0.131), despite the observed significant clinical improvement (Tables 2 and 3). sBDNF levels did not differ according to number of ECT sessions completed nor according to diagnostic group or gender. Finally, no correlations were found between T0-–T1 changes of sBDNF levels and T0–T1 changes in each clinical assessment scale scores (HDRS, BPRS, CGIs) (Table 4). Response in our sample was 100%, while only six patients met the criterion for remission (28.57%).

4. 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 of sBDNF levels with the severity of depression (Karege et al., 2002; Gonul et al., 2005). We did not find such a correlation between baseline sBDNF levels and depression severity, as assessed through the HDRS. This is in line with findings of others with plasma and serum BDNF levels, who found reduced BDNF levels without a correlation with depression levels (Lee et al., 2007; Wolkowitz et al., 2011, respectively). Differently from SSRI treatment (Wolkowitz et al., 2011), pretreatment sBDNF levels did not predict clinical response Table 3 Spearman correlations between sBDNF levels and clinical parameters of 21 TRD patients at T0 and T1. T0

Age Gender Cigarette smoking Alcohol abuse Education Duration of illness BPRS CGIs HDRS

BDNF ng/ml (mean7 S.D.) BPRS HDRS CGIs

ECT group T1

Z

P

11.8 72.81 48.0 78.21 23.2 74.16 4.43 70.51

11.17 2.54 29.7 7 5.80 8.52 7 1.72 2.197 0.68

 1.51  4.02  4.02  4.17

0.131 o 0.001 o 0.001 o 0.001

T1

ρ

P

ρ

P

 0.12 0.13  0.13  0.02  0.13 0.12 0.06  0.10  0.11

0.609 0.563 0.576 0.931 0.579 0.611 0.812 0.681 0.646

 0.11  0.11  0.07  0.02 0.07 0.36 0.43 0.36 0.52

0.633 0.644 0.780 0.931 0.579 0.105 0.052# 0.109 0.018*

Abbreviations: BPRS, Brief Psychiatric Rating Scale; CGIs, Clinical Global Impressions scale, severity; HDRS, Hamilton Depression Rating Scale; sBDNF, serum BrainDerived Nerve growth Factor; T0, baseline, prior to first electroconvulsive therapy session; T1, at completion of the electroconvulsive therapy cycle; TRD, treatmentresistant depression. #

Trend.

Table 4 Spearman correlations between sBDNF level and clinical parameter changes (T0 vs. T1).

Table 2 Comparisons between sBDNF levels and clinical parameters before and after ECT. Pvalues refer to the Wilcoxon signed-rank test. ECT group T0

3

BPRS HDRS CGIs

ρ

P

0.19  0.19 0.24

0.219 0.155 0.199

Abbreviations: BPRS, Brief Psychiatric Rating Scale; CGIs, Clinical Global Impressions scale, severity; HDRS, Hamilton Depression Rating Scale; sBDNF, serum Brain-Derived Nerve growth Factor; T0, baseline, prior to first electroconvulsive therapy session; T1, at completion of the electroconvulsive therapy cycle.

Abbreviations: BDNF, Brain-Derived Nerve growth Factor; BPRS, Brief Psychiatric Rating Scale; CGIs, Clinical Global Impressions scale, severity; ECT, electroconvulsive therapy; HDRS, Hamilton Depression Rating Scale; sBDNF, serum BrainDerived Nerve growth Factor; S.D., standard deviation.

Please cite this article as: Rapinesi, C., et al., Electroconvulsive therapy improves clinical manifestations of treatment-resistant depression without changing serum BDNF levels. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.04.009i n

P o 0.05.

4

C. Rapinesi et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎

to ECT in our study. Interestingly, Lee et al. (2007) found a positive correlation between plasma BDNF with HDRS scores in untreated patients, while we found a positive correlation between HDRS scores and sBDNF post-ECT. We are neither able to suggest why this occurred nor why there was a trend towards a positive correlation between sBDNF post-ECT and general psychopathology scores, but it is possible that a more severe psychopathological state could have elicited in the organism an attempt to adjust through increased BDNF levels. Alternatively, the lack of correlation we found may reflect the fact that the relationships between peripheral BDNF and major depressive psychopathology is much more complex than previously realized and might involve other psychoneuroendocrine mechanisms and genetic factors, like promoter methylation of the BDNF gene (Kleimann et al., 2014) and BDNF gene polymorphisms (Bousman et al., 2014). After completion of the ECT cycle, patients showed a significant improvement in depressive symptoms, as indicated by the 63.28% drop of mean HDRS scores from T0 to T1, an improvement in general psychopathology, as shown by a 38.125% drop in BPRS scores, and in severity of illness, as shown by a 50.56% reduction of CGIs scores. Despite significant clinical improvement after ECT, sBDNF levels were relatively unmodified, if not decreased. This is in line with some (Grønli et al., 2009; Fernandes et al., 2009, Fernandes et al., 2010; Gedge et al., 2012; Lin et al., 2013; Kleimann et al., 2014) but not with other findings (Bocchio-Chiavetto et al., 2006; Marano et al., 2007; Okamoto et al., 2008; Piccinni et al., 2009; Hu et al., 2010; Stelzhammer et al., 2013; Haghighi et al., 2013; Bilgen et al., 2014; Bumb et al., 2014). The reasons of inconsistency may be related to differences in study methodologies and clinical factors, including polarity of illness, presence of psychotic features, episode recurrence, and drug treatment before and during ECT cycles. Investigating plasma or sBDNF appears not to be related to a particular outcome, since with both methods, BDNF levels were found to increase significantly or not to increase after ECT. Among those three investigating post-ECT plasma BDNF, one found no increase (Lin et al., 2013) and the other two found an increase, 1 week after the last ECT session the first (Piccinni et al., 2009), and at the end of the ECT session the second (Haghighi et al., 2013). Studies using the more recommendable practice to investigate sBDNF (Elfving et al., 2010) were similarly distributed with regard to increased or not increased levels after ECT. Comparative data of studies investigating BDNF changes after ECT are shown in Table 5. Although in Haghighi et al. (2013) paper, the overview of six studies might point to differences in employed ECT methods (bilateral vs. unilateral) and in BDNF changes (elevations vs. no significant changes) between plasma and serum BDNF studies, respectively, the trend disappeared when including 13 articles (Table 5). Okamoto et al. (2008) found sBDNF post-treatment increases only in a subgroup of ECT responders, while nonresponders did not show significant sBDNF changes; we were not able to perform similar subanalyses, as all our patients were responders; however, of the six remitters we identified in our sample, five showed decreased sBDNF levels after a complete ECT cycle and only one showed a small increase. Okamoto et al. (2008) used a very similar method to ours to measure sBDNF; furthermore, their sample size was similar to ours, but its diagnostic composition was much different, and this could underlie part of the differences we observed in response to ECT and sBDNF changes. Another proportion of the differences could be accounted for by their having maintained antidepressant drugs during the ECT period, suspending only mood stabilizers, while we withdrew all drugs during the corresponding period; moreover, their sample of TRD patients was subjected to more ECT sessions than our sample (mean ECT sessions: 12 Okamoto et al. (2008) vs. 7.28 Rapinesi et al. (This issue)). It should be mentioned that the only study that kept patients without psychoactive drugs during the ECT period, found with plasma BDNF similar results to ours, i.e., post-ECT levels do not significantly change from baseline (Lin et al., 2013).

Recent evidence suggests that antidepressant drugs are able to induce platelet activation (Markovitz et al., 2000) and BDNF release, overcoming BDNF alterations which have been documented in patients with depression (Karege et al., 2005). Hence, in studies using antidepressants, the latter might have acted as a trigger for blood BDNF levels to increase, or that there was a synergistic effect between the antidepressant and ECT. In all studies (but one, Bilgen et al., 2014) in which an elevation of BDNF levels occurred post-treatment, antidepressants were given, and in the only study using drug naïve patients (Haghighi et al., 2013), antidepressant administration for 4 weeks was followed by BDNF level elevation, and ECT further potentiated this elevation. So it seems that ECT alone is unable to elevate blood BDNF (Lin et al., 2013; this study), but it may do so if there is a concurrent antidepressant enhancer (Haghighi et al., 2013). However, even when ECT was followed by sBDNF elevations in patients with antidepressants suspended, there was a lack of correlation between sBDNF changes and clinical improvement (Bilgen et al., 2014). Another source of inconsistency may be represented by method heterogeneity, as BDNF levels proved to depend on the assay used (Brunoni et al., 2008). However, the use of any type of assay could yield any result (Table 5). We could not compare the effect of diagnosis on blood BDNF levels with other studies because in many of them diagnoses were not clearly stated. Gender also would not appear to constitute a predictor. In our study we found that there was no significant sBDNF change immediately after the conclusion of an ECT cycle and that there was no correlation between sBDNF modifications and clinical response. However, it is possible that an increase in sBDNF could occur following ECT at some time after cycle completion. In fact, in one study, despite clinical improvement, sBDNF did not increase on the first day after completion of the ECT-cycle, but only 1 month later (Bocchio-Chiavetto et al., 2006). Whatever the time course of ECT-induced sBDNF elevation, it is unlikely that they may mediate clinical improvement since the latter had already occurred when sBDNF levels were low and unchanged with respect to baseline. Hence, our data are in line with the concept that sBDNF does not cause clinical improvement, but when it occurs, it might represent the result of such improvement. Our study, like that of Kleimann et al. (2014), does not confirm part of results of a recent meta-analysis showing ECT to increase blood BDNF, but do agree with the lack of correlation between BDNF level changes and clinical improvement resulting from the same meta-analysis (Brunoni et al., 2014). Even though a control group is lacking in our study, the sBDNF levels found in our sample at both T0 (11.872.81) and T1 (11.1 72.54) are lower compared to values of normal controls, which are about 16.37 77.3 ng/ml (Lang et al., 2004). Our sample was of mature to advanced age. sBDNF levels tend to decrease significantly from the twenties–thirties to the forties– fifties (Katoh-Semba et al., 2007), so the low levels we observed in our sample and the relative inability to elevate sBDNF levels after effective antidepressant treatment could have been due to a system that has become less responsive with age. In fact, the brain BDNF system elicits reduced neuroplastic responses with advancing age in the rat (Calabrese et al., 2013), and something similar could occur in the human or in depression. 4.1. Limitations of the study The sample size of our study was relatively small, hence, we cannot rule-out the possibility of false-negative results. We did not assay sBDNF at some time after the ECT cycle completion (2 weeks or 1 month) as did others, so we cannot rule-out that sBDNF levels increased after some time following an ECT cycle. But even if it was

Please cite this article as: Rapinesi, C., et al., Electroconvulsive therapy improves clinical manifestations of treatment-resistant depression without changing serum BDNF levels. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.04.009i

C. Rapinesi et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎

5

Table 5 Comparison of ECT studies investigating BDNF changes. Paper

Patients

BDNF

ECT

Concurrent drugs

Plasma BDNF Marano et al. (2007)

10 MDD, 5 BP-I (6 with PS)

ELISA ChemiKine Chemicon

Bitemporal or bifrontal, 4–10 sessions, median 7 Bilateral

ADs

Increased post-ECT

Psychotropic agents suspended

Baseline after last session

Steady increase, more in remitters (very atypical remission criteria, HDRS o10! Chosen cut-off misattributed to Lecrubier, 2002) No differences in plasma BDNF levels following ECT

Citalopram 40 mg/day

Baseline after last session

Increased in both groups; AD þ ECT significantly more than AD only

ADs at stable doses

Baseline end of cycle 1 month later

Increased at end of cycle in the low-baseline sBDNF subgroup, in the entire sample 1 month later Increased only in 12 responders, not in 6 nonresponders

Piccinni et al. 18, 2 MDD and 16 BP (8 with ELISA Promega, (2009) PS) EDTA as a chelating agent

55, 47 MDD and 8 BP (8 with ELISA Quantikine, Bilateral, 3–12 ECT sessions PS) R&D systems, with EDTA as a chelating agent Bifrontal, 12 sessions ELISA sandwich Haghighi 40 MDD drug-naïve et al. (2013) “randomized” to AD (N ¼ 20) Emax Immunoassay Kit or AD þECT (N ¼ 20); 5 with Promega with PS EDTA as a chelating agent Serum BDNF 23 MDD, 10 without and 13 ELISA Quantikine Bilateral frontoBocchiowith PS kit RD System temporal Chiavetto et al. (2006) Bilateral fronto18 MDD or BP-I (5 with PS) ELISA BDNF, Okamoto temporal, 12 Emax et al. Immunoassay Kit sessions (2008) Promega Unilateral, 8–12 ELISA two-site Grønli et al. 10 with ICD recurrent sessions enzyme (2009) depression or moderate-toimmunoassay kit severe depression or BP (Emax?) Promega Lin et al. (2013)

Fernandes et al. (2009) Fernandes et al. (2010) Hu et al. (2010)

Gedge et al. (2012)

ADs, but mood stabilizers Baseline 1 week suspended after last session

Venlafaxine (150– 225 mg/day) and/or mirtazapine (30 mg/ day) þpsychotherapy

ELISA sandwich Chemicon

Unilateral

ADs, APs

7 with refractory schizophrenia

ELISA sandwich Chemicon

28 with ICD unipolar depression, depressive episode or recurrent depression 11 with MDD

ELISA Promega

Unilateral, ECT sessions ranged from 12 to 18 Bifrontal, 6 sessions

Typical and atypical APs for at least 3 weeks before and during ECT ADs suspended

12 sessions, as “per hospital protocol” (Providence CareMental Health Services, Kingston, Ontario, Canadaa) Unilateral, 12 sessions

ADs, APs, BZDs, stable throughout study

Stelzhammer 12 MDD, TRD et al. (2013)

Multiplexed immunoassay profiling, HumanMAPs platform

Bilgen et al. (2014)

34 MDD, TRD vs. 30 healthy controls

Phoenix Peptide Human BDNF ELISA kit (EK033-22, 96 tests)

Salehi et al. (2014)

60 MDD, TRD randomized single-blind (patients knew, raters no) to ECT alone, to AET (treadmill exercise  30 min  3 times/ week) alone, and to ECT þ AET 20 MDD

Bifrontal, 12 sessions ELISA Emax Immunoassay system reagent, R&D systems-USA with EDTA as a chelating agent Unilateral or Fluorometric bilateral two-site ELISA, Promega,

Bumb et al. (2014)

Baseline any point after the 4th ECT session ADs, but mood stabilizers Baseline after the suspended 3rd session 1 week after last session

15 with DSM-IV unipolar or bipolar depression

ELISA sandwich Emax Immunoassay Kit Promega

Assessment time

Drug-free for at least 2 weeks before ECT, ECT over the first 2 weeks and a combination of ECT and ADs over the subsequent 2 weeks Bilateral-bitemporal, All psychotropic drugs 5–12 sessions suspended

BDNF modified by ECT treatment

No significant change Baseline at  5 and 0 min before ECT and 5, 15, 30 and 60 min after at 1st, 4th and 8th session Baseline after last No significant change session Baseline after last session

No significant change

Baseline after last session

Increased from low to nearnormal levels

Baseline (1 week before) 1 week after last session

No significant change, no correlation between sBDNF and HDRS scores

After the 1st ECT session after the 6th ECT session after the 12th ECT session þ2 weeks with ADs Prior to first session, at first clinical response, at the end of ECT cycle

Decreased sBDNF levels after ECT and after ECT þ AD

Citalopram 40 mg/day

Baseline after last session

Ongoing treatment unchanged during the study period

Baseline (prior to first ECT session); within a week

Compared to controls, at all three time points patients displayed lower sBDNF levels; ECT was followed by increases in sBDNF at both first clinical response and at ECT cycle conclusion; however, elevations did not relate to clinical response Increased in all groups; levels were higher in the ECT alone group, compared to ECT þ AET and to the AET alone groups

Elevations of sBDNF, which did not however correlate with clinical improvement

Please cite this article as: Rapinesi, C., et al., Electroconvulsive therapy improves clinical manifestations of treatment-resistant depression without changing serum BDNF levels. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.04.009i

C. Rapinesi et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎

6

Table 5 (continued ) Paper

Patients

Kleimann 11 MDD, TRD et al. (2014)

BDNF

ECT

Mannheim, Germany DuoSet ELISA Not specified (DY248, DY212 E, R&D Systems, WiesbadenNordenstadt, Germany)

Concurrent drugs

Assessment time

BDNF modified by ECT treatment

Ongoing treatment unchanged throughout study

after last ECT session) Before, 1, and 24 h No elevation of sBDNF after after ECT sessions ECT, no correlation with 1, 4, 7, and 10 clinical effect

Abbreviations: AD(s), antidepressant(s); AET, aerobic exercise training; AP(s), antipsychotic(s); BDNF, Brain-Derived Nerve growth Factor; BP, bipolar disorder (-I or -II); BZDs, benzodiazepines; ECT, electroconvulsive therapy; EDTA, ethylene diamine tetraacetate; ELISA, enzyme-linked immunosorbent assay; HDRS, Hamilton Depression Rating Scale; ICD, International Classification of Diseases; MDD, major depressive disorder; PS, psychotic symptoms; sBDNF, serum Brain-Derived Nerve growth Factor; TRD, treatment-resistant depression. a

Both unilateral and bilateral ECT are provided by the Hospital (see Delva et al. (2000)).

going to be so, we would not be able to attribute clinical improvement to sBDNF change, as the former would have preceded the latter; hence, our finding of a lack of correlation is strong enough for the conclusion to be drawn, that ECT induced an antidepressant effect in TRD which is not mediated through sBDNF changes. Furthermore, treatment duration varied among patients, thus adding another possible confounder. Finally, our patients did not receive concomitant antidepressant agents throughout their ECT cycles, which could possibly have contributed to the rise of BDNF following ECT; on the other hand, the possible influence on BDNF of antidepressant discontinuation before ECT cannot be ruled-out. Less than 10% of our sample were men, hence it is possible that the female gender could have played a role in our finding of low levels of sBDNF in our TRD sample. Women were shown to have lower platelet, but not plasma BDNF levels than men (Lommatzsch et al., 2005), but display higher serum levels than men (Trajkovska et al., 2007), hence it is unlikely that the low values we observed here were due to a gender bias.

5. 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 role in maintaining long-term effects of ECT in TRD.

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 manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. All authors meet criteria for authorship, has participated in the design and carrying-out of the study, and has approved its final form. Chiara Rapinesi has designed the study, wrote the paper

with Georgios D. Kotzalidis, Martina Curto, Vittoria R. Ferri, and Paolo Girardi, carried-out patients' assessments and followed them clinically, performed bibliographic searches, organized and coordinated the whole équipe, and ensured that the kits were correctly handled; Georgios D. Kotzalidis wrote the Introduction and Discussion, designed the study, conducted bibliographic searches and supervised the database; Martina Curto performed all statistical analyses and wrote the statistics part, supervised kits for BDNF assays and carried-out assays, participated extensively in the writing of the paper, and coordinated the serum assay équipe; Vittoria R. Ferri participated in study design, wrote parts of Introduction, Materials and Methods, and Discussion, and performed bibliographic searches; Daniele Serata followed-up patients, performed bibliographic searches, and participated in discussions about the paper's form; Paola Scatena followed patients, performed ECTs, and participated in the writing of the manuscript; Paolo Carbonetti followed-up patients and performed ECTs; Flavia Napoletano participated in reviewing the paper and in the writing of the serum BDNF assay part; Jessica Miele performed assays and participated in writing the BDNF assay part; Sergio Scaccianoce performed and supervised assays and participated in the writing of the BDNF assay part; Antonio Del Casale participated in the design, wrote parts of the Methods, and supervised the database; Ferdinando Nicoletti designed the study, supervised assay and wrote parts of the Methods; Gloria Angeletti participated in the design of the study, followed-up patients, and coordinated the clinical équipe; Paolo Girardi participated in study design, assessed patients, supervised the entire study and its writing. This work has not been supported by any funding.

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. References Altar, C.A., Whitehead, R.E., Chen, R., Wörtwein, G., Madsen, T.M., 2003. Effects of electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain. Biological Psychiatry 54, 703–709. American Psychiatric Association, 2000. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision (DSM-IV-TR). American Psychiatric Association, Washington, D.C. Aydemir, O., Deveci, A., Taneli, F., 2005. The effect of chronic antidepressant treatment on serum brain-derived neurotrophic factor levels in depressed

Please cite this article as: Rapinesi, C., et al., Electroconvulsive therapy improves clinical manifestations of treatment-resistant depression without changing serum BDNF levels. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.04.009i

C. Rapinesi et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎ patients: a preliminary study. Progress in Neuro-Psychopharmacology and Biological Psychiatry 29, 261–265. Berton, O., Nestler, E.J., 2006. New approaches to antidepressant drug discovery: beyond monoamines. Nature Reviews Neuroscience 7, 137–151. Bilgen, A.E., Bozkurt Zincir, S., Zincir, S., Ozdemir, B., Ak, M., Aydemir, E., Sener, I., 2014. Effects of electroconvulsive therapy on serum levels of brain-derived neurotrophic factor and nerve growth factor in treatment resistant major depression. Brain Research Bulletin 104, 82–87. Bocchio-Chiavetto, L., Zanardini, R., Bortolomasi, M., Abate, M., Segala, M., Giacopuzzi, M., Riva, M.A.,, Marchina, E., Pasqualetti, P., Perez, J., Gennarelli, M., 2006. Electroconvulsive Therapy (ECT) increases serum Brain Derived Neurotrophic Factor (BDNF) in drug resistant depressed patients. European Neuropsychopharmacology 16, 620–624. Bousman, C.A., Katalinic, N., Martin, D.M., Smith, D.J., Ingram, A., Dowling, N., Ng, C., Loo, C.K., 2014. Effects of COMT, DRD2, BDNF, and APOE genotypic variation on treatment efficacy and cognitive side effects of electroconvulsive therapy. Journal of ECT , http://dx.doi.org/10.1097/YCT.0000000000000170 [Epub ahead of print]. Brent, D., Melhem, N., Turecki, G., 2010. Pharmacogenomics of suicidal events. Pharmacogenomics 11, 793–807. Brunoni, A.R., Lopes, M., Fregni, F., 2008. A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression. International Journal of Neuropsychopharmacology 11, 1169–1180. Brunoni, A.R., Baeken, C., Machado-Vieira, R., Gattaz, W.F., Vanderhasselt, M.A., 2014. BDNF blood levels after electroconvulsive therapy in patients with mood disorders: a systematic review and meta-analysis. World Journal of Biological Psychiatry 15, 411–418. Bumb, J.M., Aksay, S.S., Janke, C., Kranaster, L., Geisel, O., Gass, P., Hellweg, R., Sartorius, A., 2014. Focus on ECT seizure quality: serum BDNF as a peripheral biomarker in depressed patients. European Archives of Psychiatry and Clinical Neuroscience, http://dx.doi.org/10.1007/s00406-014-0543-3. Calabrese, F., Guidotti, G., Racagni, G., Riva, M.A., 2013. Reduced neuroplasticity in aged rats: a role for the neurotrophin brain-derived neurotrophic factor. Neurobiology of Aging 34, 2768–2776. Delva, N.J., Brunet, D., Hawken, E.R., Kesteven, R.M., Lawson, J.S., Lywood, D.W., Rodenburg, M., Waldron, J.J., 2000. Electrical dose and seizure threshold: relations to clinical outcome and cognitive effects in bifrontal, bitemporal, and right unilateral ECT. Journal of ECT 16, 361–369. Duman, R.S., Vaidya, V.A., 1998. Molecular and cellular actions of chronic electroconvulsive seizures. Journal of ECT 14, 181–193. Duman, R.S., Heninger, G.R., Nestler, E.J., 1997. A molecular and cellular theory of depression. Archives of General Psychiatry 54, 597–606. Elfving, B., Plougmann, P.H., Wegener, G., 2010. Detection of brain-derived neurotrophic factor (BDNF) in rat blood and brain preparations using ELISA: pitfalls and solutions. Journal of Neuroscience Methods 187, 73–77. Fava, G.A., Ruini, C., Sonino, N., 2003. Treatment of recurrent depression: a sequential psychotherapeutic and psychopharmacological approach. CNS Drugs 17, 1109–1117. Fernandes, B., Gama, C.S., Massuda, R., Torres, M., Camargo, D., Kunz, M., Belmontede-Abreu, P.S., Kapczinski, F., de Almeida Fleck, M.P., Inês Lobato, M., 2009. Serum brain-derived neurotrophic factor (BDNF) is not associated with response to electroconvulsive therapy (ECT): a pilot study in drug resistant depressed patients. Neuroscience Letters 453, 195–198. Fernandes, B.S., Massuda, R., Torres, M., Camargo, D., Fries, G.R., Gama, C.S., Belmonte-de-Abreu, P.S., Kapczinski, F., Lobato, M.I., 2010. Improvement of schizophrenia with electroconvulsive therapy and serum brain-derived neurotrophic factor levels: Lack of association in a pilot study. Psychiatry and Clinical Neurosciences 64, 663–665. Fernandes, B.S., Gama, C.S., Ceresér, K.M., Yatham, L.N., Fries, G.R., Colpo, G., de Lucena, D., Kunz, M., Gomes, F.A., Kapczinski, F., 2011. Brain-derived neurotrophic factor as a state-marker of mood episodes in bipolar disorders: a systematic review and meta-regression analysis. Journal of Psychiatric Research 45, 995–1004. Fujimura, H., Altar, C.A., Chen, R., Nakamura, T., Nakahashi, T., Kambayashi, J., Sun, B., Tandon, N.N., 2002. Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation. Thrombosis and Haemostasis 87, 728–734. Gedge, L., Beaudoin, A., Lazowski, L., du Toit, R., Jokic, R., Milev, R., 2012. Effects of electroconvulsive therapy and repetitive transcranial magnetic stimulation on serum brain-derived neurotrophic factor levels in patients with depression. Frontiers in Psychiatry 3, 12. Gonul, A.S., Akdeniz, F., Taneli, F., Donat, O., Eker, Ç., Vahip, S., 2005. Effect of treatment on serum brain-derived neurotrophic factor levels in depressed patients. European Archives of Psychiatry and Clinical Neuroscience 255, 381–386. Grønli, O., Stensland, G.Ø., Wynn, R., Olstad, R., 2009. Neurotrophic factors in serum following ECT: a pilot study. World Journal of Biological Psychiatry 10, 295–301. Guy, W., 1976. ECDEU Assessment Manual of Psychopharmacology — Revised. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, NIMH Psychopharmacology Research Branch, Division of Extramural Research Programs, Rockville, MD, USA, pp. 217–222 (DHEW Publ No ADM 76-338). Haghighi, M., Salehi, I., Erfani, P., Jahangard, L., Bajoghli, H., Holsboer-Trachsler, E., Brand, S., 2013. Additional ECT increases BDNF-levels in patients suffering from

7

major depressive disorders compared to patients treated with citalopram only. Journal of Psychiatric Research 47, 908–915. Hamilton, M., 1960. A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry 23, 56–62. Hestad, K.A., Tønseth, S., Støen, C.D., Ueland, T., Aukrust, P., 2003. Raised plasma levels of tumor necrosis factor alpha in patients with depression: normalization during electroconvulsive therapy. Journal of ECT 19, 183–188. Hu, Y., Yu, X., Yang, F., Si, T., Wang, W., Tan, Y., Zhou, D., Wang, H., Chen, D., 2010. The level of serum brain-derived neurotrophic factor is associated with the therapeutic efficacy of modified electroconvulsive therapy in Chinese patients with depression. Journal of ECT 26, 121–125. Huang, T.L., Lee, C.T., Liu, Y.L., 2008. Serum brain-derived neurotrophic factor levels in patients with major depression: effects of antidepressants. Journal of Psychiatric Research 42, 521–525. Hussain, F., Cochrane, R., 2004. Depression in South Asian women living in the UK: a review of the literature with implications for service provision. Transcultural Psychiatry 41, 253–270. Karege, F., Perret, G., Bondolfi, G., Schwald, M., Bertschy, G., Aubry, J.M., 2002. Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Research 109, 143–148. Karege, F., Bondolfi, G., Gervasoni, N., Schwald, M., Aubry, J.M., Bertschy, G., 2005. Low brain-derived neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity. Biological Psychiatry 57, 1068–1072. Katoh-Semba, R., Wakako, R., Komori, T., Shigemi, H., Miyazaki, N., Ito, H., Kumagai, T., Tsuzuki, M., Shigemi, K., Yoshida, F., Nakayama, A., 2007. Age-related changes in BDNF protein levels in human serum: differences between autism cases and normal controls. International Journal of Developmental Neuroscience 25, 367–372. Kleimann, A., Kotsiari, A., Sperling, W., Gröschl, M., Heberlein, A., Kahl, K.G., Hillemacher, T., Bleich, S., Kornhuber, J., Frieling, H., 2014. BDNF serum levels and promoter methylation of BDNF exon I, IV and VI in depressed patients receiving electroconvulsive therapy. Journal of Neural Transmission , http://dx. doi.org/10.1007/s00702-014-1336-6 [Epub ahead of print]. Klein, A.B., Williamson, R., Santini, M.A., Clemmensen, C., Ettrup, A., Rios, M., Knudsen, G.M., Aznar, S., 2011. Blood BDNF concentrations reflect brain-tissue BDNF levels across species. International Journal of Neuropsychopharmacology 14, 347–353. Lang, U.E., Hellweg, R., Gallinat, J., 2004. BDNF serum concentrations in healthy volunteers are associated with depression-related personality traits. Neuropsychopharmacology 29, 795–798. Laske, C., Eschweiler, G.W., 2006. Brain-derived neurotrophic factor. Vom Nervenwachstumsfaktor zum Plastizitätsmodulator bei kognitiven Prozessen und psychischen Erkrankungen [Brain-derived neurotrophic factor: from nerve growth factor to modulator of brain plasticity in cognitive processes and psychiatric diseases]. Nervenarzt 77, 523–537. Lecrubier, Y., 2002. How do you define remission? Acta Psychiatrica Scandinavica 106 (Supplement 415), S7–S11. Lee, B.H., Kim, H., Park, S.H., Kim, Y.K., 2007. Decreased plasma BDNF level in depressive patients. Journal of Affective Disorders 101, 239–244. Lin, C.H., Chen, M.C., Lee, W.K., Chen, C.C., Huang, C.H., Lane, H.Y., 2013. Electroconvulsive therapy improves clinical manifestation with plasma BDNF levels unchanged in treatment-resistant depression patients. Neuropsychobiology 68, 110–115. Lommatzsch, M., Zingler, D., Schuhbaeck, K., Schloetcke, K., Zingler, C., SchuffWerner, P., Virchow, J.C., 2005. The impact of age, weight and gender on BDNF levels in human platelets and plasma. Neurobiology of Aging 26, 115–123. Marano, C.M., Phatak, P., Vemulapalli, U.R., Sasan, A., Nalbandyan, M.R., Ramanujam, S., Soekadar, S., Demosthenous, M., Regenold, W.T., 2007. Increased plasma concentration of brain-derived neurotrophic factor with electroconvulsive therapy: a pilot study in patients with major depression. Journal of Clinical Psychiatry 68, 512–517. Markovitz, J.H., Shuster, J.L., Chitwood, W.S., May, R.S., Tolbert, L.C., 2000. Platelet activation in depression and effects of sertraline treatment: an open-label study. American Journal of Psychiatry 157, 1006–1008. Matrisciano, F., Bonaccorso, S., Ricciardi, A., Scaccianoce, S., Panaccione, I., Wang, L., Ruberto, A., Tatarelli, R., Nicoletti, F., Girardi, P., Shelton, R.C., 2009. Changes in BDNF serum levels in patients with major depression disorder (MDD) after 6 months treatment with sertraline, escitalopram, or venlafaxine. Journal of Psychiatric Research 43, 247–254. Mikoteit, T., Beck, J., Eckert, A., Hemmeter, U., Brand, S., Bischof, R., HolsboerTrachsler, E., Delini-Stula, A., 2014. High baseline BDNF serum levels and early psychopathological improvement are predictive of treatment outcome in major depression. Psychopharmacology 231, 2955–2965. Molendijk, M.L., Bus, B.A., Spinhoven, P., Penninx, B.W., Kenis, G., Prickaerts, J., Voshaar, R.C., Elzinga, B.M., 2011. Serum levels of brain-derived neurotrophic factor in major depressive disorder: state-trait issues, clinical features and pharmacological treatment. Molecular Psychiatry 16, 1088–1095. Newton, S.S., Girgenti, M.J., Collier, E.F., Duman, R.S., 2006. Electroconvulsive seizure increases adult hippocampal angiogenesis in rats. European Journal of Neuroscience 24, 819–828. Okamoto, T., Yoshimura, R., Ikenouchi-Sugita, A., Hori, H., Umene-Nakano, W., Inoue, Y., Ueda, N., Nakamura, J., 2008. Efficacy of electroconvulsive therapy is associated with changing blood levels of homovanillic acid and brain-derived neurotrophic factor (BDNF) in refractory depressed patients: a pilot study.

Please cite this article as: Rapinesi, C., et al., Electroconvulsive therapy improves clinical manifestations of treatment-resistant depression without changing serum BDNF levels. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.04.009i

8

C. Rapinesi et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎

Progress in Neuro-Psychopharmacology and Biological Psychiatry 32, 1185–1190. Ongür, D., Pohlman, J., Dow, A.L., Eisch, A.J., Edwin, F., Heckers, S., Cohen, B.M., Patel, T.B., Carlezon Jr., W.A., 2007. Electroconvulsive seizures stimulate glial proliferation and reduce expression of Sprouty2 within the prefrontal cortex of rats. Biological Psychiatry 62, 505–512. Overall, J.E., 1974. Psychological measurements in psychopharmacology. Modern Problems in Pharmacopsychiatry 7, 67–78. Overall, J.E., Gorham, D.R., 1962. The Brief Psychiatric Rating Scale. Psychological Reports 10, 799–812. Piccinni, A., Del Debbio, A., Medda, P., Bianchi, C., Roncaglia, I., Veltri, A., Zanello, S., Massimetti, E., Origlia, N., Domenici, L., Marazziti, D., Dell’Osso, L., 2009. Plasma brain-derived neurotrophic factor in treatment-resistant depressed patients receiving electroconvulsive therapy. European Neuropsychopharmacology 19, 349–355. Salehi, I., Hosseini, S.M., Haghighi, M., Jahangard, L., Bajoghli, H., Gerber, M., Pühse, U., Kirov, R., Holsboer-Trachsler, E., Brand, S., 2014. Electroconvulsive therapy and aerobic exercise training increased BDNF and ameliorated depressive symptoms in patients suffering from treatment-resistant major depressive disorder. Journal of Psychiatric Research 57, 117–124. Scott, B.W., Wojtowicz, J.M., Burnham, W.M., 2000. Neurogenesis in the dentate gyrus of the rat following electroconvulsive shock seizures. Experimental Neurology 165, 231–236. Sen, S., Duman, R., Sanacora, G., 2008. Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biological Psychiatry 64, 527–532.

Shimizu, E., Hashimoto, K., Okamura, N., Koike, K., Komatsu, N., Kumakiri, C., Nakazato, M., Watanabe, H., Shinoda, N., Okada, S., Iyo, M., 2003. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biological Psychiatry 54, 70–75. Stelzhammer, V., Guest, P.C., Rothermundt, M., Sondermann, C., Michael, N., Schwarz, E., Rahmoune, H., Bahn, S., 2013. Electroconvulsive therapy exerts mainly acute molecular changes in serum of major depressive disorder patients. European Neuropsychopharmacology 23, 1199–1207. Swartz, C.M., Abrams, R., 1996. ECT Instruction Manual, Somatics Inc., 6th ed.. Taliaz, D., Stall, N., Dar, D.E., Zangen, A., 2010. Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis. Molecular Psychiatry 15, 80–92. Taliaz, D., Loya, A., Gersner, R., Haramati, S., Chen, A., Zangen, A., 2011. Resilience to chronic stress is mediated by hippocampal brain-derived neurotrophic factor. Journal of Neuroscience 31, 4475–4483. Trajkovska, V., Marcussen, A.B., Vinberg, M., Hartvig, P., Aznar, S., Knudsen, G.M., 2007. Measurements of brain-derived neurotrophic factor: methodological aspects and demographical data. Brain Research Bulletin 73, 143–149. Wahlund, B., von Rosen, D., 2003. ECT of major depressed patients in relation to biological and clinical variables: a brief overview. Neuropsychopharmacology 28 (Supplement 1), S21–S26. Wolkowitz, O.M., Wolf, J., Shelly, W., Rosser, R., Burke, H.M., Lerner, G.K., Reus, V.I., Nelson, J.C., Epel, E.S., Mellon, S.H., 2011. Serum BDNF levels before treatment predict SSRI response in depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry 35, 1623–1630. Yamamoto, H., Gurney, M.E., 1990. Human platelets contain brain-derived neurotrophic factor. Journal of Neuroscience 10, 3469–3478.

Please cite this article as: Rapinesi, C., et al., Electroconvulsive therapy improves clinical manifestations of treatment-resistant depression without changing serum BDNF levels. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.04.009i