Brain Research Bulletin 104 (2014) 82–87
Contents lists available at ScienceDirect
Brain Research Bulletin journal homepage: www.elsevier.com/locate/brainresbull
Research report
Effects of electroconvulsive therapy on serum levels of brain-derived neurotrophic factor and nerve growth factor in treatment resistant major depression Ali Emrah Bilgen a , Selma Bozkurt Zincir b,∗ , Serkan Zincir c , Barbaros Özdemir d , Mehmet Ak e , Emre Aydemir d , I˙ rfan S¸ener f a
Etimesgut Asker Hastanesi, Department of Psychiatry, Ankara, Turkey Erenkoy Training and Research Hospital for Psychiatric and Neurological Disorders, Department of Psychiatry, I˙ stanbul, Turkey c Gölcük Asker Hastanesi, Department of Psychiatry, Kocaeli, Turkey d Gülhane Askeri Tıp Akademisi, Department of Psychiatry, Ankara, Turkey e Memorial Hospital, Department of Psychiatry, Konya, Turkey f Gülhane Askeri Tıp Akademisi, Department of Biochemistry, Ankara, Turkey b
a r t i c l e
i n f o
Article history: Received 11 December 2013 Received in revised form 6 April 2014 Accepted 7 April 2014 Available online 18 April 2014 Keywords: Major depression Electroconvulsive therapy Brain-derived neurotrophic factor Nerve growth factor
a b s t r a c t Objectives: This study aimed to investigate the effects of electroconvulsive treatment on serum BDNF and NGF levels in patients with treatment-resistant major depression. Methods: Thirty patients with treatment-resistant major depression and 30 healthy controls were included in the study. The patients’ serum BDNF and NGF levels were measured three times; before treatment (T0), when the clinical response occurred (T1) and at the end of treatment (T2). Results: The reduction detected in the HAM-D scores with ECT during the T0–T1, T1–T2 and T0–T2 periods was found to be statistically significant. In the patient group, increase in the mean BDNF levels after ECT treatment was found to be statistically significant (p < 0.05). Significant increases in serum BDNF levels with ECT were lower than in the control group, and the serum NGF levels did not increase significantly. There was no relationship between the severity of the depression and serum BDNF and NGF levels (p > 0.05). Conclusions: This study evaluated the role of neurotrophic factors in the etiopathogenesis of major depression. Future studies should investigate the relationship between neurotrophic factors with neuroendocrine and genetic processes to elucidate the psychobiology and treatment of mental disorders. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Major depression, which can be quite common and recurrent, is a mood disorder that may disrupt the quality of life and social cohesion of the person, and it may have serious consequences, such as chronicity and suicide. Major depression will be the second most important cause of disability in the world by the year 2020 (Murray
∗ Corresponding author at: 19 Mayıs Mah. Sinan Ercan Caddesi, No: 29 Kazasker, I˙ stanbul 34736, Turkey. Tel.: +90 533 660 18 93; fax: +90 216 356 05 03. E-mail addresses: dr [email protected] (A.E. Bilgen), [email protected] (S. Bozkurt Zincir), [email protected] (S. Zincir), [email protected] (B. Özdemir), [email protected] (M. Ak), [email protected] (E. Aydemir), dr [email protected] (I˙ . S¸ener). http://dx.doi.org/10.1016/j.brainresbull.2014.04.005 0361-9230/© 2014 Elsevier Inc. All rights reserved.
and Lopez, 1997). However, the aetiology of major depression is still unclear today. The first theory that was raised about the biological aetiology of depression was the “monoamine hypothesis.” However, the presence of treatment-resistant depression despite the success of antidepressants in increasing synaptic monoamine levels within hours, the late emergence of the treatment effectiveness has placed this hypothesis into question. Today, despite the fact that monoamine levels and the number of receptors are apparently normal, a disruption at the molecular level has been proposed in the distal of the signal transduction pathways of monoamines and their receptors, and the BDNF gene has been targeted as a candidate mechanism (Stahl, 2012). The reduction in the volume of the hippocampus was observed in patients with recurrent or resistant and long-lasting depressive episodes, and no volume change in younger patients with fewer
A.E. Bilgen et al. / Brain Research Bulletin 104 (2014) 82–87
depressive episodes and a shorter duration of disease. Therefore, depression may be directly associated with significant structural changes and degeneration in some parts of the brain (hippocampus, amygdala and prefrontal cortex in particular) with the synaptic activity changes of neurochemicals such as monoamines. On the basis of this assumption, the “neuroplasticity hypothesis” has been proposed (Kotan et al., 2009; Sala et al., 2004). Neuroplasticity can be defined as changes in the structural properties and functions of the neurons and synapses in the brain that depend on various internal and external stimuli. Neurotrophic factors are important intracellular molecules for neuroplasticity. Additionally, they have a very important role in the survival of neurons in sustaining their life and fulfilling their functions. While serving as neurotransmitters in the central nervous system (CNS), neurotrophic factors simultaneously assist in the development and renovation of neurons. They also have an important role in the programming and execution of cell death. The group of well-defined molecules among the neurotrophic factors called neurotrophins consists of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin 3 (NT-3) and neurotrophin 4 (NT-4) (Carvey, 1998). BDNF plays an important role in brain development and plasticity by neurogenesis, synaptic plasticity, and supporting cell viability. In the process of the development of the cerebral cortex and hippocampus, BDNF triggers the differentiation of neural stem cells into neurons and supports the survival of neurons in the next generation (Lee et al., 2002). The neuroplasticity hypothesis is supported by preclinical and clinical studies that show that depressive disorders lead to a reduction in hippocampal volume and a loss of cells in the limbic system. The alleged cell death mechanisms in depressive disorders include: neurotrophic damage mechanisms, increases in the levels of glucocorticoids and excitatory neurotransmitters, glial cell changes and the inhibition of secondary neurogenesis. According to the neurotrophin hypothesis, BDNF has great importance due to the regulation of plasticity, inhibition of cell death cycles and the increase in proteins for cell survival in life (Yulu˘g et al., 2009). Studies showing that depressive states generated in animal models are associated with decreased BDNF levels in the brain and that central BDNF implementation improves the depressed state support this hypothesis (Reus et al., 2011; Shirayama et al., 2002). The number of clinical trials referring to the relationship between depressive disorders and BDNF is gradually increasing. In many studies, serum BDNF levels of patients with major depression without treatment were found to be significantly lower than those of the control group (Karege et al., 2002a,b; Bocchio-Chiavetto et al., 2010). Studies that detected low BDNF levels increased after antidepressant treatment (Gönül et al., 2005; Aydemir et al., 2005; Brunoni et al., 2008). From this point, it was expressed that BDNF may be “final common pathway” for different antidepressant approaches, and chronic antidepressant treatment accelerated neurogenesis in the adult hippocampus and organized the cyclic adenosine monophosphate (cAMP) and neurotrophin signalling pathways, which have roles in cellular plasticity and survival (Yulu˘g et al., 2009). In the literature, the low serum BDNF levels in patients with major depression compared to the control group as increased by antidepressant treatment were considered to be significant, but it is difficult to conclude the same for NGF with the current findings. The first neurotrophic factor, NGF, is not as widely studied as BDNF in the current literature on major depression. It is thought that it plays a role in synaptic plasticity in the adult brain. There are few studies in the literature about NGF levels in major depression and its exchange with treatment, and animal studies often provide contradictory results. (Reus et al., 2011; Schulte-Herbruggen et al., 2009; Angelucci et al., 2000; Martino et al., 2013; Xiong et al., 2011).
83
Although ECT is a very effective method of treatment for treatment-resistant major depression, its mechanism of action is still not clear. Nowadays, low BDNF serum levels in major depression and their increase with antidepressant treatment have warranted much attention regarding ECT’s effects on neurotrophic factors (BDNF, NGF). In the literature, the limited number of studies investigating the effect of ECT on neurotrophic factors has typically focused on BDNF, and NGF has been neglected. These studies have yielded conflicting results (Angelucci et al., 2003; Haghighi et al., 2013; Kim et al., 2010; Bocchio-Chiavetto et al., 2006; Fernandes et al., 2009). For these reasons, our study compared the effects of ECT on neurotrophic factors (BDNF, NGF) in patients with treatment-resistant major depression with a control group, conducting evaluations at three different times: before ECT, when a clinical response occurred, and after ECT. At the same time, the relationship between changes in neurotrophic factors with ECT and decreases in the severity of depression were investigated.
2. Methods 2.1. Subjects The study sample was composed of treatment-resistant major depression inpatients treated with ECT in the Department of Psychiatry in Gülhane Military Medical School Hospital between March 2011 and July 2012 and healthy control groups. A total of 34 treatment-resistant major depressive disorder patients (12 males, 22 females) treated with ECT and 30 healthy controls (10 males, 20 females) were included in the study. Four patients with no response to ECT treatment after 12 sessions (50% or greater reduction in the HAM-D scale compared to baseline values) were excluded. A total of 30 patients (11 men, 19 women) completed the study. Patients were diagnosed according to the DSM-IV diagnostic criteria by applying a semi-structured clinical interview for DSM-IV Axis I disorders (SCID-I, Structured Clinical Interview for DSM-Axis 1 Disorders) and disease severity were evaluated with the 17-item Hamilton Depression Rating Scale (HAM-D-Hamilton Depression Rating Scale). Before the study, socio-demographic data forms for both the patient and the control groups (age, education level, marital status, alcohol and drug abuse, the presence of a family history of psychiatric illness, physical or psychiatric illness, suicide attempts, antidepressants and psychotropic drug history, number of attacks and the duration of end-stage disease) were completed. The concept of resistance to therapy has been recognized as unresponsive antidepressant therapy at the appropriate dose and period of time from two different groups (Nierenberg and Amsterdam, 1990). During the ECT treatment, psychotropic drugs (antidepressants, antipsychotics, etc.) were not used so as to avoid disturbing the seizure threshold in terms of the ECT, as well as to avoid confounding factors that affect the BDNF and NGF levels (only to determine the effect of ECT). To provide sedation or to resolve agitation, a benzodiazepine (on ECT treatment days) and hydroxyzine was used if necessary. From all participants, written informed consent was obtained for both the use of ECT treatment and for participation in the study. Those with a comorbid Axis I diagnosis (including bipolar depression), with any organic disturbance histories or examinations; a history of psychoactive substance use in the last month; mental retardation; an acute or chronic infection in the last month; any medication use in the last 6 weeks, including psychotropic drugs and non-steroidal anti-inflammatory drugs; autoimmune, allergic, neoplastic, or endocrine disease states, including the status of the heart or brain surgery and infarcts; patients with any risky situation for ECT; patients who failed to respond to at the end of
84
A.E. Bilgen et al. / Brain Research Bulletin 104 (2014) 82–87
the twelve sessions of ECT treatment; a family history of suicide; and those with a history of major depression (control group) were excluded. 2.2. Application and sample collection The necessary tests and consultations requested by the clinical team for the planned ECT treatment for treatment-resistant patients diagnosed with major depression by SCID-I with a risky situation were investigated. The HAM-D scale was applied three different times; pre-ECT (one day before treatment – T0), clinical response to ECT (HAM-D scale compared to baseline values were determined as a reduction of 50% or more – T1) and at the end of ECT treatment (T2) (the day after the treatment – T2) to patients who met the criteria to be included in the study without any contraindications to ECT treatment, and venous blood samples were taken to measure the levels of NGF and BDNF. In the control group, venous blood samples were taken only once to measure the levels of BDNF and NGF. 2.2.1. ECT application ECT was carried out by a team composed of an anaesthesiologist, a psychiatrist, a psychiatric nurse and anaesthesia technicians at the ECT division of the Department of Psychiatry. Subsequent to a period of fasting (8–12 h) after standard anaesthesia monitoring, patient-specific doses of propofol (0.75–1 mg/kg) for anaesthesia induction and the muscle relaxant succinylcholine (1 mg/kg) were applied intravenously to all patients by the anaesthesiologist. In the ECT application, the formation of 25 s of long-term convulsions was targeted by administering square wave-type pulses of 550–800 mA of current (stimulus width 1–2 ms, frequency 40–90 Hz, with a the 0.5–4 s, maximum 1172 mC charge) with the bilateral-bitemporal method using Mecta Spectrum 5000Q brand ECT device. If necessary, for the formation of active convulsions, more than one current was applied in the same session, and the seizure period was determined by the method of coupling. The number of ECT applications in our study was between 5 and 12 for a total of 3 times a week, and this number could be increased or decreased by the patient’s clinical response. In our study, ECT was terminated when an additional improvement was not observed in the clinical response after a second session, including the maximum number of 12. 2.2.2. Measurement of BDNF and NGF Between the hours of 08:00 and 10:00 in the morning after 8–12 h of fasting, 5-mL blood samples were taken from an antecubital vein from both patients and control subjects. The samples taken for measurement of BDNF and NGF were transferred to straight tubes without anticoagulants after standing at 4.0 ◦ C for 4 h, and they were then centrifuged for 15 min at 3000 cycles. Sera was placed into Eppendorf tubes and stored until analysis at −80 ◦ C. BDNF measurements were made with the Phoenix Peptide Human BDNF ELISA kit (EK-033-22, 96 tests), and the measurement of NGF was made by NGF Human Raybiotech Elisa kit (ELH-BNGF-001, 96 tests) with the ELISA method as described with the Bio-Tek Synergy HT microplate reader and kit package inserts. 2.3. Statistical analyses SPSS version 15.00 (SPSS Inc., Chicago, IL, United States) was used for data analysis. Continuous variables were assigned as means ± standard deviation, while discrete variables were assigned as numbers and percentages. Whether continuous variables complied with a normal distribution was checked with the Kolmogorov–Smirnov test. Whether the groups differed in terms of discrete variables was checked by Pearson’s chi-square test. Where
Fig. 1. Changes in serum BDNF and NGF levels with ECT treatment.
continuous variables did not comply with a normal distribution, the Kruskal–Wallis test was used for multiple-group comparisons, and the Bonferroni corrected Mann–Whitney U test was used for post hoc comparison. When comparing the two groups for continuous variables, if parametric conditions were met, Student’s t test was applied, and if parametric conditions were not met, the Mann–Whitney U test was used. A paired-samples t test was applied to compare dependent groups (measurements), while Pearson’s correlation test was used in the assessment of relationships between variables. A p value below 0.05 was considered to be statistically significant.
3. Results 3.1. Socio-demographic characteristics The study was completed by 30 treatment-resistant major depression patients. The data of the patient group was compared with the data of a control group of 30 healthy volunteers. No statistically significant difference was found between these two groups in terms of age, sex, marital status and education level. The sociodemographic characteristics of the patient and control groups are compared in Table 1. 3.2. Clinical scales and changes with treatment Pre-ECT treatment (T0) mean of the HAM-D score of patients was 30.66 ± 4.11; the T1 period HAM-D mean score was 15.73 ± 3.36; and the T2 period HAM-D mean was 12.93 ± 4.98. The reduction detected in the HAM-D scores with ECT during the T0–T1, T1–T2 and T0–T2 periods was found to be statistically significant (T0–T1: t = 38.65, p < 0.05; T0–T2: t = 21.64, p < 0.05; T1–T2: t = 4.14, p < 0.05; t: t test in dependent groups). 3.3. BDNF and NGF measurements For 30 treatment-resistant major depression patients, the pretreatment mean BDNF levels were 1990.46 (s.d.: ± 510.18) pq/ml and the mean NGF level was 399.36 (s.d.: ± 91.69) pq/ml, while in the control group, the mean BDNF level was 3128.86 (s.d.: ± 445.21) pq/ml, and the mean NGF level was 524.10 (s.d.: ± 76.71) pq/ml. Pre-treatment BDNF and NGF levels of the patient group were found to be significantly lower than the corresponding levels in the control group (BDNF: t = −9.208, p < 0.005; NGF: −5.714, p < 0.05). No significant correlation was found considering the pre-treatment neurotrophic factor (BDNF, NGF) levels, sociodemographic data (age, sex, family history, marital status, suicide history, etc.) and the HAM-D scores of the patient group. The mean BDNF and NGF levels of patient group in the T0, T1, T2 periods by ECT treatment are given in Fig. 1.
A.E. Bilgen et al. / Brain Research Bulletin 104 (2014) 82–87
85
Table 1 Socio-demographic and clinical characteristics of patient and control groups. Major depression (n = 30) Sex (n, %) Male Female Age; mean ± s.d.b (years) Education level (n, %) Elementary school High school University Marital status (n, %) Married Single Family history (n, %) Yes No Suicide history (n, %) Yes No No. of episodes; mean ± s.d. (min–max) Duration of last episode; mean ± s.d. (min–max, months) No. of ECT; mean ± s.d. (min–max) c T1 ECT number; mean ± s.d. (min–max) a b c
11 (36.7) 19 (63.3) 33 ± 5.9
Control (n = 30) 10 (33.3) 20 (66.7) 31.2 ± 5.5
7 (23.3) 15 (50.0) 8 (26.7)
5 (16.7) 17 (56.7) 8 (26.7)
13 (43.3) 17 (56.7)
17 (56.7) 13 (43.3)
10 (33.3) 20 (66.7)
a
t/2
p
0.073
0.78
1.203
0.23
0.45
0.79
0.302 1.067
–
12 (40) 18 (60) 2.9 ± 1.9 (1–8) 6.1 ± 1.3 (4–9) 8.6 ± 1.7 (5–12) 5.06 ± 0.8 (3–7)
– – – – –
t = Student’s t test, 2 = Pearson’s chi-square test. Mean ± s.d. = mean ± standard deviation, min = minimum, max = maximum. T1 = no. of ECTs applied until the receipt of a clinical response.
3.4. Relationship between HAM-D scores and BDNF and NGF measurements In the patient group, after ECT treatment, a statistically significant correlation was not found between BDNF and NGF levels (T1, T2) on one side and HAM-D scores (T1, T2) on the other side. A statistically significant correlation was also not found between the increase in BDNF and NGF levels and the reduction in HAM-D scores. In the patient group, the mean BDNF levels showed an increase after ECT treatment in all periods (T0–T1, T1–T2, T0–T2), and the increases in the T0–T1, T1–T2, T0–T2 periods were found to be statistically significant (T0–T1: t = −4.56, p < 0.05; T1–T2: t = −2.75, p < 0.05; T0–T2: t = −9.78, p < 0.05). Furthermore, when the BDNF values in both the T1 and T2 periods were compared to those of the control group, the levels in the patient group were found to be significantly low (Table 2). A review of the mean NGF levels in the patient group reveals that though NGF levels increased with ECT treatment in the T0–T1 and T0–T2 periods, they were slightly reduced in the T1–T2 period. However, the increases in the T0–T1 and T0–T2 periods and the reduction in the T1–T2 period were not found to be statistically significant (T0–T1: t = −2.03, p > 0.05; T1–T2: t = 0.16, p > 0.05; T0–T2: t = −1.69, p > 0.05). Furthermore, when NGF values in both the T1 and T2 periods were compared to those of the control group, the levels in the patient group were found to be significantly low (Table 2).
4. Discussion This study is a prospective, non-randomized and controlled study examining the effects of ECT treatment on serum neurotrophic factor levels in treatment-resistant major depression patients. In the present study, pre-treatment BDNF and NGF levels in the treatment-resistant major depression group were found to be lower than the control group. It was further determined that ECT treatment increased BDNF and NGF levels, but only the increase in BDNF levels was statistically significant. Although it was considered that ECT reduces the severity of major depression, after ECT, no significant relationship was found between the reduction in severity of major depression (reduction in HAM-D scores) and the increases in BDNF and NGF levels.
4.1. BDNF and NGF measurements In our study, in the patient group, the baseline serum BDNF and NGF levels were found to be lower when compared to those of the control group. This result is generally consistent with the results of animal studies that studied neurotrophin levels in major depression in the literature (Reus et al., 2011; Angelucci et al., 2000). Just as in animal experiments, in human studies, it has been specified that low BDNF levels may play an important role in the pathophysiology of major depressive disorder (Karege et al., 2002a,b; Gönül et al., 2005; Brunoni et al., 2008). Serum BDNF levels in major depression were found to be significantly lower than those in the control group. On the other hand, in light of the available findings, it is difficult to say the same thing for serum NGF levels. Similarly, studies not only show that serum NGF levels in major depression are lower than those in the control group, but other studies show that the same levels are higher (Martino et al., 2013; Xiong et al., 2011; Hadjiconstantinou et al., 2001). 4.2. Changes in BDNF and NGF after treatment It was noted that the literature contains only a few studies that review the effects of ECT treatment on neurotrophic factors, and only the study conducted by Grönli et al. (2009) examined BDNF and NGF levels together. Different from our study, all three studies conducted by Fernandes et al. (2009), Grönli et al. (2009) and Gedge et al. (2012) have reported that ECT treatment does not have any significant effect on BDNF or NGF levels (Fernandes et al., 2009; Gedge et al., 2012; Grönli et al., 2009). In other studies, consistent with our study, it was emphasized that ECT treatment leads to a statistically significant increase in serum or plasma BDNF levels (Haghighi et al., 2013; Bocchio-Chiavetto et al., 2006; Piccinni et al., 2009; Hu et al., 2010). These studies are affected by important factors that may methodologically affect the results. In most studies, bipolar depression patients were included. Particularly in studies conducted on bipolar depression patients, it was noted that the number of patients included in the study was low. In some groups, the control group consisted of patients taking antidepressants, while no control group was used in some others. In all studies but one, patients underwent continued antidepressant treatment during the study.
86
A.E. Bilgen et al. / Brain Research Bulletin 104 (2014) 82–87
Table 2 Comparison of BDNF and NGF levels after ECT in patient and control groups. Patient (n = 30) BDNF T1 (mean ± s.d.) BDNF T2 (mean ± s.d.) NGF T1 (mean ± s.d.) NGF T2 (mean ± s.d.)
2464.63 2713.33 443.96 439.66
± ± ± ±
431.72 382.89 83.93 128.97
Control (n = 30) 3128.86 3128.86 524.10 524.10
± ± ± ±
445.21 445.21 76.71 76.71
t
p
−5.86 −3.87 −3.86 −3.08
0.000* 0.000* 0.000* 0.003*
T1 = when the clinical response to ECT treatment was received, T2 = post-ECT treatment, t = Student’s t test. * p < 0.05.
Serum BDNF levels were measured in some studies, while plasma BDNF levels were measured in others. The time of assessment of neurotrophin levels and the clinical scale differed. Likewise, it is believed that differences in the form of ECT application, the anaesthetic substances used, the centrifuge and storage of blood samples in the laboratory, the measurement kits used, etc. may also affect the results. This suggests that there may be differences that arise out of methodological differences between the results of our study and those of other studies. It is envisaged that a more significant increase may be observed in serum BDNF and NGF levels only in studies with a wider sample. The effects of factors such as sex and age on serum BDNF and NGF levels could not be evaluated precisely in our study due to our small sample. Another important point that might have affected the results of studies is that in all studies but one Hu et al. (2010), the patients continued to take antidepressants. As mentioned earlier, antidepressant treatment led to a rise in BDNF levels. Piccinni et al. (2009) reported that the baseline plasma BDNF levels in the remission group were higher when compared to the corresponding levels in the non-remission group. However, in their study, such higher baseline plasma BDNF levels in the remission group may be related with antidepressant treatment. In our study, on the other hand, patients were not given antidepressant treatment. Thus, antidepressant medication had no effect at all in the elevation of BDNF levels. In contrast, the drugs used, such as benzodiazepines and hydroxyzine, may also have some reducing effects on serum BDNF and NGF levels (Huopaniemi et al., 2004; Huang and Hung, 2009). 4.3. Clinical scales and change with ECT After ECT treatment, a statistically significant reduction was detected in the severity of depression (in HAM-D scores). This result is consistent with the findings of other similar studies in the literature (Haghighi et al., 2013; Hu et al., 2010; Okamoto et al., 2008). In the literature, contradictory results have been reported by other similar studies. In some studies, a correlation was not detected consistently with the results of our study (Haghighi et al., 2013; Gedge et al., 2012). On the other hand, other studies have asserted that there exists a positive correlation between the serum and plasma BDNF levels and the recovery of depression symptoms (Piccinni et al., 2009; Hu et al., 2010; Okamoto et al., 2008). Hu et al. (2010) also reported a positive correlation between the increase in serum BDNF levels and the recovery in cognitive dysfunction and retardation sub-groups in the HAM-D scale. 4.4. Limitations of study One of the main limitations of our study was our small sample. However, in comparison to other similar studies, the size of our sample may be the equivalent or larger. But, nevertheless, the significance of a correlation between the more significant increase in serum BDNF and NGF levels after ECT treatment and the reduction in the severity of depression and serum neurotrophin levels requires new studies with larger samples. Furthermore, the size of
our sample is insufficient to assess the effects of such factors as sex and age on serum neurotrophin levels as well. Bus et al. (2011) reported that in addition to sex and age, such factors as smoking and alcohol, the time the blood sample was taken, the time until the sample is processed, how much time after the meal the blood sample was taken, exercise, the menstrual cycle, and the characteristics of the storage environment of the sample are also effective on serum neurotrophin levels (Bus et al., 2011). In our study, the failure to assess the effects of smoking and the menstrual characteristics of female patients, representing the majority of the sample, may be considered a limitation. As discussed in the similar studies, the time needed for the occurrence of a significant increase in neurotrophins such as BDNF and NGF by treatment (antidepressant or ECT treatment) is still unclear. Therefore, in future studies, we believe that more meaningful results may be reached through a longer post-treatment follow-up period. In our study, the failure to separately group the patients according to remission criterion upon the completion of treatment may also be considered a limitation. The negative correlation between the significant increase in serum BDNF and NGF levels reaching the same level with the control group and the severity of depression and serum neurotrophin levels may be demonstrated in the future through studies classifying remission and non-remission patients. Haghighi et al. (2013) reported that the failure to find a relationship between plasma BNDF levels and recovery in the severity of depression may be explained by genetic factors such as BNDF Val66Met gene polymorphism. In our study, the failure to check BDNF gene polymorphisms (particularly Val66Met) may also be considered to be a limitation. The determination of the effects of ECT or antidepressant treatments on neurotrophin levels should be supported by genetic-based studies.
5. Conclusions This study is important because it is the first study conducted in our country to examine the effects of ECT treatment on serum neurotrophin levels. In addition, the examination of NGF levels, which seem to have lost their importance regarding BDNF, is also believed to contribute to the literature. Whether BDNF may be a biological indicator in the diagnosis of major depression and in monitoring the response to treatment is still a matter of debate among researchers. The fact that in major depression, BDNF is lower than in healthy volunteers and rises with treatment, while this rise is not observed in patients who do not respond to treatment, makes BDNF an indicator. However, it is affected by many stress-related psychological and medical disorders, reducing the specificity of BDNF for major depression. A review of the findings obtained so far reveals that it is difficult to declare that BDNF and NGF are specific indicators for major depression. In the future, studies assessing the neurotrophic factors together with neuro-endocrinologic and genetic processes may help to elucidate psycho-biological characteristics of psychological disorders, particularly major depression.
A.E. Bilgen et al. / Brain Research Bulletin 104 (2014) 82–87
Disclosure The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. References Angelucci, F., Aloe, L., Vasquez, P.J., Mathe, A.A., 2000. Mapping the differences in the brain concentration of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in an animal model of depression. Neuroreport 27, 1369–1373. Angelucci, F., Aloe, L., Jimenez-Vasquez, P., Mathe, A.A., 2003. Electroconvulsive stimuli alter nerve growth factor but not brain-derived neurotrophic factor concentrations in brains of a rat model of depression. Neuropeptides 37, 51–56. Aydemir, O., Deveci, A., Taneli, F., 2005. The effect of chronic antidepressant treatment on serum brain-derived neurotrophic factor levels in depressed patients: a preliminary study. Prog. Neuropsychopharmacol. Biol. Psychiatry 29, 261–265. Bocchio-Chiavetto, L., Bagnardi, V., Zanardini, R., Molteni, R., Nielsen, M.G., Placentino, A., 2010. Serum and plasma BDNF levels in major depression: a replication study and meta-analyses. World J. Biol. Psychiatry 11, 763–773. Bocchio-Chiavetto, L., Zanardini, R., Bortolomasi, M., Abate, M., Segala, M., Giacopuzzi, M., 2006. Electroconvulsive Therapy (ECT) increases serum brain derived neurotrophic factor (BDNF) in drug resistant depressed patients. Eur. Neuropsychopharmacol. 16, 620–624. Bus, B.A., Molendijk, M.L., Penninx, B.J., Buitelaar, J.K., Kenis, G., Prickaerts, J., 2011. Determinants of serum brain-derived neurotrophic factor. Psychoneuroendocrinology 36, 228–239. Brunoni, A.R., Lopes, M., Frengi, 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. Int. J. Neuropsychopharmacol. 11, 1169–1180. Carvey, P.M., 1998. Drug Action in the Central Nervous System. Oxford University, New York, pp. 123–150. Fernandes, B., Gama, C.S., Massuda, R., Torres, M., Camargo, D., Kunz, 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. Neurosci. Lett. 453, 195–198. 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. Front. Psychiatry 12. Gönül, A.S., Akdeniz, F., Taneli, F., Donat, O., Eker, C., Vahip, S., 2005. Effect of treatment on serum brain-derived neurotrophic factor levels in depressed patients. Eur. Arch. Psychiatry Clin. Neurosci. 255, 381–386. Grönli, O., Stensland, G.O., Wynn, R., Olstad, R., 2009. Neurotrophic factors in serum following ECT: a pilot study. World J. Biol. Psychiatry 10, 295–301. Hadjiconstantinou, M., Mcguire, L., Duchemin, A.M., Laskowski, B., Kiecolt-Glaser, J., Glaser, R., 2001. Changes in plasma NGF levels in older adults associated with chronic stress. J. Neuroimmunol. 116, 102–106. Haghighi, M., Salehi, I., Erfani, P., Jahangard, L., Bajoghli, H., Holsboer-Trachsler, E., 2013. Additional ECT increases BDNF-levels in patients suffering from major depressive disorders compared to patients treated with citalopram only. J. Psychiatr. Res. 47, 908–915. Hu, Y., Yu, X., Yang, F., Si, T., Wang, W., Tan, Y., 2010. The level of serum brain-derived neurotrophic factor is associated with the therapeutic efficacy of modified electroconvulsive therapy in Chinese patients with depression. J. ECT 26, 121–125.
87
Huang, T.L., Hung, Y.Y., 2009. Lorazepam reduces the serum brain-derived neurotrophic factor level in schizophrenia patients with catatonia. Prog. Neuropsychopharmacol. Biol. Psychiatry 33, 158–159. Huopaniemi, L., Keist, R., Randolph, A., Certa, U., Rudolph, U., 2004. Diazepaminduced adaptive plasticity revealed by ␣1 GABA-A receptor-specific expression profiling. J. Neurochem. 88, 1059–1067. Karege, F., Perret, G., Bondolfi, G., Schwald, M., Bertschy, G., Aubry, J.M., 2002a. Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res. 109, 143–148. Karege, F., Schwald, M., Cisse, M., 2002b. Postnatal developmental profile of brainderived neurotrophic factor in rat brain and platelets. Neurosci. Lett. 328, 261–264. Kim, J., Gale, K., Kondratyev, A., 2010. Effects of repeated minimal electroshock seizures on NGF, BDNF and FGF-2 protein in the rat brain during postnatal development. Int. J. Dev. Neurosci. 28, 227–232. Kotan, Z., Sarandöl, A., Saygın, E.S., Akkaya, C., 2009. Depression, neuroplasticity and neurotrophic factors. Curr. Approach. Psychiatry 1, 22–35. Lee, J., Duan, W., Mattson, M.P., 2002. Evidence that brain-derived neuro-trophic factor is required for basal neurogenesis and mediates in part the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J. Neurochem. 82, 1367–1375. Martino, M., Rocchi, G., Escelsior, A., Contini, P., Colicchio, S., de Berardis, D., 2013. NGF serum levels variations in major depressed patients receiving duloxetine. Psychoneuroendocrinology 13, 47–54. Murray, C.J., Lopez, A.D., 1997. Alternative projections of mortality and disability by cause 1990–2020. Global Burden of Disease Study. Lancet 349, 1498–1504. Nierenberg, A.A., Amsterdam, J.D., 1990. Treatment-resistant depression: definition and treatment approaches. J. Clin. Psychiatry 51, 39–47, discussion 48–50. Okamoto, T., Yoshimura, R., Ikenouchi-Sugita, A., Hori, H., Umene-Nakano, W., Inoue, Y., 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. Prog. Neuropsychopharmacol. Biol. Psychiatry 32, 1185–1190. Piccinni, A., Del Debbio, A., Medda, P., Bianchi, C., Roncaglia, I., Veltri, A., 2009. Plasma Brain-Derived Neurotrophic Factor in treatment-resistant depressed patients receiving ECT. Eur. Neuropsychopharmacol. 19, 349–355. Reus, G.Z., Stringari, R.B., Ribeiro, K.F., Cipriano, A.L., Panizzutti, B.S., Stertz, L., 2011. Maternal deprivation induces depressive-like behaviour and alters neurotrophin levels in the rat brain. Eurochem. Res. 36, 460–466. Sala, M., Perez, J., Soloff, P., Ucelli di Nemi, S., Caverzasi, E., Soares, J.C., 2004. Stress and hippocampal abnormalities in psychiatric disorders. Eur. Neuropsychopharmacol. 14, 393–405. Schulte-Herbruggen, O., Fuchs, E., Abumaria, N., Ziegler, A., Danker-Hopfe, H., Hiemke, C., 2009. Effects of escitalopram on the regulation of brain-derived neurotrophic factor and nerve growth factor protein levels in a rat model of chronic stress. J. Neurosci. Res. 87, 2551–2560. Shirayama, Y., Chen, A.C., Nakagawa, S., Russell, D.S., Duman, R.S., 2002. Brainderived neurotrophic factor produces antidepressant effects in behavioral models of depression. J. Neurosci. 22, 3251–3261. Stahl, S.M., (T. Uzbay, Trans.) 2012. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications, 3rd ed. Istanbul Medical Publishing. Xiong, P., Zeng, Y., Wan, J., Xiaohan, D.H., Tan, D., Lu, J., 2011. The role of NGF and IL-2 serum level in assisting the diagnosis in first episode schizophrenia. Psychiatry Res. 189, 72–76. Yulu˘g, B., Ozan, E., Gönül, A.S., Kilic¸, E., 2009. Brain derived neurotrophic factor, stress and depression: a minireview. Brain Res. Bull. 78, 267–269.
Contents lists available at ScienceDirect
Brain Research Bulletin journal homepage: www.elsevier.com/locate/brainresbull
Research report
Effects of electroconvulsive therapy on serum levels of brain-derived neurotrophic factor and nerve growth factor in treatment resistant major depression Ali Emrah Bilgen a , Selma Bozkurt Zincir b,∗ , Serkan Zincir c , Barbaros Özdemir d , Mehmet Ak e , Emre Aydemir d , I˙ rfan S¸ener f a
Etimesgut Asker Hastanesi, Department of Psychiatry, Ankara, Turkey Erenkoy Training and Research Hospital for Psychiatric and Neurological Disorders, Department of Psychiatry, I˙ stanbul, Turkey c Gölcük Asker Hastanesi, Department of Psychiatry, Kocaeli, Turkey d Gülhane Askeri Tıp Akademisi, Department of Psychiatry, Ankara, Turkey e Memorial Hospital, Department of Psychiatry, Konya, Turkey f Gülhane Askeri Tıp Akademisi, Department of Biochemistry, Ankara, Turkey b
a r t i c l e
i n f o
Article history: Received 11 December 2013 Received in revised form 6 April 2014 Accepted 7 April 2014 Available online 18 April 2014 Keywords: Major depression Electroconvulsive therapy Brain-derived neurotrophic factor Nerve growth factor
a b s t r a c t Objectives: This study aimed to investigate the effects of electroconvulsive treatment on serum BDNF and NGF levels in patients with treatment-resistant major depression. Methods: Thirty patients with treatment-resistant major depression and 30 healthy controls were included in the study. The patients’ serum BDNF and NGF levels were measured three times; before treatment (T0), when the clinical response occurred (T1) and at the end of treatment (T2). Results: The reduction detected in the HAM-D scores with ECT during the T0–T1, T1–T2 and T0–T2 periods was found to be statistically significant. In the patient group, increase in the mean BDNF levels after ECT treatment was found to be statistically significant (p < 0.05). Significant increases in serum BDNF levels with ECT were lower than in the control group, and the serum NGF levels did not increase significantly. There was no relationship between the severity of the depression and serum BDNF and NGF levels (p > 0.05). Conclusions: This study evaluated the role of neurotrophic factors in the etiopathogenesis of major depression. Future studies should investigate the relationship between neurotrophic factors with neuroendocrine and genetic processes to elucidate the psychobiology and treatment of mental disorders. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Major depression, which can be quite common and recurrent, is a mood disorder that may disrupt the quality of life and social cohesion of the person, and it may have serious consequences, such as chronicity and suicide. Major depression will be the second most important cause of disability in the world by the year 2020 (Murray
∗ Corresponding author at: 19 Mayıs Mah. Sinan Ercan Caddesi, No: 29 Kazasker, I˙ stanbul 34736, Turkey. Tel.: +90 533 660 18 93; fax: +90 216 356 05 03. E-mail addresses: dr [email protected] (A.E. Bilgen), [email protected] (S. Bozkurt Zincir), [email protected] (S. Zincir), [email protected] (B. Özdemir), [email protected] (M. Ak), [email protected] (E. Aydemir), dr [email protected] (I˙ . S¸ener). http://dx.doi.org/10.1016/j.brainresbull.2014.04.005 0361-9230/© 2014 Elsevier Inc. All rights reserved.
and Lopez, 1997). However, the aetiology of major depression is still unclear today. The first theory that was raised about the biological aetiology of depression was the “monoamine hypothesis.” However, the presence of treatment-resistant depression despite the success of antidepressants in increasing synaptic monoamine levels within hours, the late emergence of the treatment effectiveness has placed this hypothesis into question. Today, despite the fact that monoamine levels and the number of receptors are apparently normal, a disruption at the molecular level has been proposed in the distal of the signal transduction pathways of monoamines and their receptors, and the BDNF gene has been targeted as a candidate mechanism (Stahl, 2012). The reduction in the volume of the hippocampus was observed in patients with recurrent or resistant and long-lasting depressive episodes, and no volume change in younger patients with fewer
A.E. Bilgen et al. / Brain Research Bulletin 104 (2014) 82–87
depressive episodes and a shorter duration of disease. Therefore, depression may be directly associated with significant structural changes and degeneration in some parts of the brain (hippocampus, amygdala and prefrontal cortex in particular) with the synaptic activity changes of neurochemicals such as monoamines. On the basis of this assumption, the “neuroplasticity hypothesis” has been proposed (Kotan et al., 2009; Sala et al., 2004). Neuroplasticity can be defined as changes in the structural properties and functions of the neurons and synapses in the brain that depend on various internal and external stimuli. Neurotrophic factors are important intracellular molecules for neuroplasticity. Additionally, they have a very important role in the survival of neurons in sustaining their life and fulfilling their functions. While serving as neurotransmitters in the central nervous system (CNS), neurotrophic factors simultaneously assist in the development and renovation of neurons. They also have an important role in the programming and execution of cell death. The group of well-defined molecules among the neurotrophic factors called neurotrophins consists of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin 3 (NT-3) and neurotrophin 4 (NT-4) (Carvey, 1998). BDNF plays an important role in brain development and plasticity by neurogenesis, synaptic plasticity, and supporting cell viability. In the process of the development of the cerebral cortex and hippocampus, BDNF triggers the differentiation of neural stem cells into neurons and supports the survival of neurons in the next generation (Lee et al., 2002). The neuroplasticity hypothesis is supported by preclinical and clinical studies that show that depressive disorders lead to a reduction in hippocampal volume and a loss of cells in the limbic system. The alleged cell death mechanisms in depressive disorders include: neurotrophic damage mechanisms, increases in the levels of glucocorticoids and excitatory neurotransmitters, glial cell changes and the inhibition of secondary neurogenesis. According to the neurotrophin hypothesis, BDNF has great importance due to the regulation of plasticity, inhibition of cell death cycles and the increase in proteins for cell survival in life (Yulu˘g et al., 2009). Studies showing that depressive states generated in animal models are associated with decreased BDNF levels in the brain and that central BDNF implementation improves the depressed state support this hypothesis (Reus et al., 2011; Shirayama et al., 2002). The number of clinical trials referring to the relationship between depressive disorders and BDNF is gradually increasing. In many studies, serum BDNF levels of patients with major depression without treatment were found to be significantly lower than those of the control group (Karege et al., 2002a,b; Bocchio-Chiavetto et al., 2010). Studies that detected low BDNF levels increased after antidepressant treatment (Gönül et al., 2005; Aydemir et al., 2005; Brunoni et al., 2008). From this point, it was expressed that BDNF may be “final common pathway” for different antidepressant approaches, and chronic antidepressant treatment accelerated neurogenesis in the adult hippocampus and organized the cyclic adenosine monophosphate (cAMP) and neurotrophin signalling pathways, which have roles in cellular plasticity and survival (Yulu˘g et al., 2009). In the literature, the low serum BDNF levels in patients with major depression compared to the control group as increased by antidepressant treatment were considered to be significant, but it is difficult to conclude the same for NGF with the current findings. The first neurotrophic factor, NGF, is not as widely studied as BDNF in the current literature on major depression. It is thought that it plays a role in synaptic plasticity in the adult brain. There are few studies in the literature about NGF levels in major depression and its exchange with treatment, and animal studies often provide contradictory results. (Reus et al., 2011; Schulte-Herbruggen et al., 2009; Angelucci et al., 2000; Martino et al., 2013; Xiong et al., 2011).
83
Although ECT is a very effective method of treatment for treatment-resistant major depression, its mechanism of action is still not clear. Nowadays, low BDNF serum levels in major depression and their increase with antidepressant treatment have warranted much attention regarding ECT’s effects on neurotrophic factors (BDNF, NGF). In the literature, the limited number of studies investigating the effect of ECT on neurotrophic factors has typically focused on BDNF, and NGF has been neglected. These studies have yielded conflicting results (Angelucci et al., 2003; Haghighi et al., 2013; Kim et al., 2010; Bocchio-Chiavetto et al., 2006; Fernandes et al., 2009). For these reasons, our study compared the effects of ECT on neurotrophic factors (BDNF, NGF) in patients with treatment-resistant major depression with a control group, conducting evaluations at three different times: before ECT, when a clinical response occurred, and after ECT. At the same time, the relationship between changes in neurotrophic factors with ECT and decreases in the severity of depression were investigated.
2. Methods 2.1. Subjects The study sample was composed of treatment-resistant major depression inpatients treated with ECT in the Department of Psychiatry in Gülhane Military Medical School Hospital between March 2011 and July 2012 and healthy control groups. A total of 34 treatment-resistant major depressive disorder patients (12 males, 22 females) treated with ECT and 30 healthy controls (10 males, 20 females) were included in the study. Four patients with no response to ECT treatment after 12 sessions (50% or greater reduction in the HAM-D scale compared to baseline values) were excluded. A total of 30 patients (11 men, 19 women) completed the study. Patients were diagnosed according to the DSM-IV diagnostic criteria by applying a semi-structured clinical interview for DSM-IV Axis I disorders (SCID-I, Structured Clinical Interview for DSM-Axis 1 Disorders) and disease severity were evaluated with the 17-item Hamilton Depression Rating Scale (HAM-D-Hamilton Depression Rating Scale). Before the study, socio-demographic data forms for both the patient and the control groups (age, education level, marital status, alcohol and drug abuse, the presence of a family history of psychiatric illness, physical or psychiatric illness, suicide attempts, antidepressants and psychotropic drug history, number of attacks and the duration of end-stage disease) were completed. The concept of resistance to therapy has been recognized as unresponsive antidepressant therapy at the appropriate dose and period of time from two different groups (Nierenberg and Amsterdam, 1990). During the ECT treatment, psychotropic drugs (antidepressants, antipsychotics, etc.) were not used so as to avoid disturbing the seizure threshold in terms of the ECT, as well as to avoid confounding factors that affect the BDNF and NGF levels (only to determine the effect of ECT). To provide sedation or to resolve agitation, a benzodiazepine (on ECT treatment days) and hydroxyzine was used if necessary. From all participants, written informed consent was obtained for both the use of ECT treatment and for participation in the study. Those with a comorbid Axis I diagnosis (including bipolar depression), with any organic disturbance histories or examinations; a history of psychoactive substance use in the last month; mental retardation; an acute or chronic infection in the last month; any medication use in the last 6 weeks, including psychotropic drugs and non-steroidal anti-inflammatory drugs; autoimmune, allergic, neoplastic, or endocrine disease states, including the status of the heart or brain surgery and infarcts; patients with any risky situation for ECT; patients who failed to respond to at the end of
84
A.E. Bilgen et al. / Brain Research Bulletin 104 (2014) 82–87
the twelve sessions of ECT treatment; a family history of suicide; and those with a history of major depression (control group) were excluded. 2.2. Application and sample collection The necessary tests and consultations requested by the clinical team for the planned ECT treatment for treatment-resistant patients diagnosed with major depression by SCID-I with a risky situation were investigated. The HAM-D scale was applied three different times; pre-ECT (one day before treatment – T0), clinical response to ECT (HAM-D scale compared to baseline values were determined as a reduction of 50% or more – T1) and at the end of ECT treatment (T2) (the day after the treatment – T2) to patients who met the criteria to be included in the study without any contraindications to ECT treatment, and venous blood samples were taken to measure the levels of NGF and BDNF. In the control group, venous blood samples were taken only once to measure the levels of BDNF and NGF. 2.2.1. ECT application ECT was carried out by a team composed of an anaesthesiologist, a psychiatrist, a psychiatric nurse and anaesthesia technicians at the ECT division of the Department of Psychiatry. Subsequent to a period of fasting (8–12 h) after standard anaesthesia monitoring, patient-specific doses of propofol (0.75–1 mg/kg) for anaesthesia induction and the muscle relaxant succinylcholine (1 mg/kg) were applied intravenously to all patients by the anaesthesiologist. In the ECT application, the formation of 25 s of long-term convulsions was targeted by administering square wave-type pulses of 550–800 mA of current (stimulus width 1–2 ms, frequency 40–90 Hz, with a the 0.5–4 s, maximum 1172 mC charge) with the bilateral-bitemporal method using Mecta Spectrum 5000Q brand ECT device. If necessary, for the formation of active convulsions, more than one current was applied in the same session, and the seizure period was determined by the method of coupling. The number of ECT applications in our study was between 5 and 12 for a total of 3 times a week, and this number could be increased or decreased by the patient’s clinical response. In our study, ECT was terminated when an additional improvement was not observed in the clinical response after a second session, including the maximum number of 12. 2.2.2. Measurement of BDNF and NGF Between the hours of 08:00 and 10:00 in the morning after 8–12 h of fasting, 5-mL blood samples were taken from an antecubital vein from both patients and control subjects. The samples taken for measurement of BDNF and NGF were transferred to straight tubes without anticoagulants after standing at 4.0 ◦ C for 4 h, and they were then centrifuged for 15 min at 3000 cycles. Sera was placed into Eppendorf tubes and stored until analysis at −80 ◦ C. BDNF measurements were made with the Phoenix Peptide Human BDNF ELISA kit (EK-033-22, 96 tests), and the measurement of NGF was made by NGF Human Raybiotech Elisa kit (ELH-BNGF-001, 96 tests) with the ELISA method as described with the Bio-Tek Synergy HT microplate reader and kit package inserts. 2.3. Statistical analyses SPSS version 15.00 (SPSS Inc., Chicago, IL, United States) was used for data analysis. Continuous variables were assigned as means ± standard deviation, while discrete variables were assigned as numbers and percentages. Whether continuous variables complied with a normal distribution was checked with the Kolmogorov–Smirnov test. Whether the groups differed in terms of discrete variables was checked by Pearson’s chi-square test. Where
Fig. 1. Changes in serum BDNF and NGF levels with ECT treatment.
continuous variables did not comply with a normal distribution, the Kruskal–Wallis test was used for multiple-group comparisons, and the Bonferroni corrected Mann–Whitney U test was used for post hoc comparison. When comparing the two groups for continuous variables, if parametric conditions were met, Student’s t test was applied, and if parametric conditions were not met, the Mann–Whitney U test was used. A paired-samples t test was applied to compare dependent groups (measurements), while Pearson’s correlation test was used in the assessment of relationships between variables. A p value below 0.05 was considered to be statistically significant.
3. Results 3.1. Socio-demographic characteristics The study was completed by 30 treatment-resistant major depression patients. The data of the patient group was compared with the data of a control group of 30 healthy volunteers. No statistically significant difference was found between these two groups in terms of age, sex, marital status and education level. The sociodemographic characteristics of the patient and control groups are compared in Table 1. 3.2. Clinical scales and changes with treatment Pre-ECT treatment (T0) mean of the HAM-D score of patients was 30.66 ± 4.11; the T1 period HAM-D mean score was 15.73 ± 3.36; and the T2 period HAM-D mean was 12.93 ± 4.98. The reduction detected in the HAM-D scores with ECT during the T0–T1, T1–T2 and T0–T2 periods was found to be statistically significant (T0–T1: t = 38.65, p < 0.05; T0–T2: t = 21.64, p < 0.05; T1–T2: t = 4.14, p < 0.05; t: t test in dependent groups). 3.3. BDNF and NGF measurements For 30 treatment-resistant major depression patients, the pretreatment mean BDNF levels were 1990.46 (s.d.: ± 510.18) pq/ml and the mean NGF level was 399.36 (s.d.: ± 91.69) pq/ml, while in the control group, the mean BDNF level was 3128.86 (s.d.: ± 445.21) pq/ml, and the mean NGF level was 524.10 (s.d.: ± 76.71) pq/ml. Pre-treatment BDNF and NGF levels of the patient group were found to be significantly lower than the corresponding levels in the control group (BDNF: t = −9.208, p < 0.005; NGF: −5.714, p < 0.05). No significant correlation was found considering the pre-treatment neurotrophic factor (BDNF, NGF) levels, sociodemographic data (age, sex, family history, marital status, suicide history, etc.) and the HAM-D scores of the patient group. The mean BDNF and NGF levels of patient group in the T0, T1, T2 periods by ECT treatment are given in Fig. 1.
A.E. Bilgen et al. / Brain Research Bulletin 104 (2014) 82–87
85
Table 1 Socio-demographic and clinical characteristics of patient and control groups. Major depression (n = 30) Sex (n, %) Male Female Age; mean ± s.d.b (years) Education level (n, %) Elementary school High school University Marital status (n, %) Married Single Family history (n, %) Yes No Suicide history (n, %) Yes No No. of episodes; mean ± s.d. (min–max) Duration of last episode; mean ± s.d. (min–max, months) No. of ECT; mean ± s.d. (min–max) c T1 ECT number; mean ± s.d. (min–max) a b c
11 (36.7) 19 (63.3) 33 ± 5.9
Control (n = 30) 10 (33.3) 20 (66.7) 31.2 ± 5.5
7 (23.3) 15 (50.0) 8 (26.7)
5 (16.7) 17 (56.7) 8 (26.7)
13 (43.3) 17 (56.7)
17 (56.7) 13 (43.3)
10 (33.3) 20 (66.7)
a
t/2
p
0.073
0.78
1.203
0.23
0.45
0.79
0.302 1.067
–
12 (40) 18 (60) 2.9 ± 1.9 (1–8) 6.1 ± 1.3 (4–9) 8.6 ± 1.7 (5–12) 5.06 ± 0.8 (3–7)
– – – – –
t = Student’s t test, 2 = Pearson’s chi-square test. Mean ± s.d. = mean ± standard deviation, min = minimum, max = maximum. T1 = no. of ECTs applied until the receipt of a clinical response.
3.4. Relationship between HAM-D scores and BDNF and NGF measurements In the patient group, after ECT treatment, a statistically significant correlation was not found between BDNF and NGF levels (T1, T2) on one side and HAM-D scores (T1, T2) on the other side. A statistically significant correlation was also not found between the increase in BDNF and NGF levels and the reduction in HAM-D scores. In the patient group, the mean BDNF levels showed an increase after ECT treatment in all periods (T0–T1, T1–T2, T0–T2), and the increases in the T0–T1, T1–T2, T0–T2 periods were found to be statistically significant (T0–T1: t = −4.56, p < 0.05; T1–T2: t = −2.75, p < 0.05; T0–T2: t = −9.78, p < 0.05). Furthermore, when the BDNF values in both the T1 and T2 periods were compared to those of the control group, the levels in the patient group were found to be significantly low (Table 2). A review of the mean NGF levels in the patient group reveals that though NGF levels increased with ECT treatment in the T0–T1 and T0–T2 periods, they were slightly reduced in the T1–T2 period. However, the increases in the T0–T1 and T0–T2 periods and the reduction in the T1–T2 period were not found to be statistically significant (T0–T1: t = −2.03, p > 0.05; T1–T2: t = 0.16, p > 0.05; T0–T2: t = −1.69, p > 0.05). Furthermore, when NGF values in both the T1 and T2 periods were compared to those of the control group, the levels in the patient group were found to be significantly low (Table 2).
4. Discussion This study is a prospective, non-randomized and controlled study examining the effects of ECT treatment on serum neurotrophic factor levels in treatment-resistant major depression patients. In the present study, pre-treatment BDNF and NGF levels in the treatment-resistant major depression group were found to be lower than the control group. It was further determined that ECT treatment increased BDNF and NGF levels, but only the increase in BDNF levels was statistically significant. Although it was considered that ECT reduces the severity of major depression, after ECT, no significant relationship was found between the reduction in severity of major depression (reduction in HAM-D scores) and the increases in BDNF and NGF levels.
4.1. BDNF and NGF measurements In our study, in the patient group, the baseline serum BDNF and NGF levels were found to be lower when compared to those of the control group. This result is generally consistent with the results of animal studies that studied neurotrophin levels in major depression in the literature (Reus et al., 2011; Angelucci et al., 2000). Just as in animal experiments, in human studies, it has been specified that low BDNF levels may play an important role in the pathophysiology of major depressive disorder (Karege et al., 2002a,b; Gönül et al., 2005; Brunoni et al., 2008). Serum BDNF levels in major depression were found to be significantly lower than those in the control group. On the other hand, in light of the available findings, it is difficult to say the same thing for serum NGF levels. Similarly, studies not only show that serum NGF levels in major depression are lower than those in the control group, but other studies show that the same levels are higher (Martino et al., 2013; Xiong et al., 2011; Hadjiconstantinou et al., 2001). 4.2. Changes in BDNF and NGF after treatment It was noted that the literature contains only a few studies that review the effects of ECT treatment on neurotrophic factors, and only the study conducted by Grönli et al. (2009) examined BDNF and NGF levels together. Different from our study, all three studies conducted by Fernandes et al. (2009), Grönli et al. (2009) and Gedge et al. (2012) have reported that ECT treatment does not have any significant effect on BDNF or NGF levels (Fernandes et al., 2009; Gedge et al., 2012; Grönli et al., 2009). In other studies, consistent with our study, it was emphasized that ECT treatment leads to a statistically significant increase in serum or plasma BDNF levels (Haghighi et al., 2013; Bocchio-Chiavetto et al., 2006; Piccinni et al., 2009; Hu et al., 2010). These studies are affected by important factors that may methodologically affect the results. In most studies, bipolar depression patients were included. Particularly in studies conducted on bipolar depression patients, it was noted that the number of patients included in the study was low. In some groups, the control group consisted of patients taking antidepressants, while no control group was used in some others. In all studies but one, patients underwent continued antidepressant treatment during the study.
86
A.E. Bilgen et al. / Brain Research Bulletin 104 (2014) 82–87
Table 2 Comparison of BDNF and NGF levels after ECT in patient and control groups. Patient (n = 30) BDNF T1 (mean ± s.d.) BDNF T2 (mean ± s.d.) NGF T1 (mean ± s.d.) NGF T2 (mean ± s.d.)
2464.63 2713.33 443.96 439.66
± ± ± ±
431.72 382.89 83.93 128.97
Control (n = 30) 3128.86 3128.86 524.10 524.10
± ± ± ±
445.21 445.21 76.71 76.71
t
p
−5.86 −3.87 −3.86 −3.08
0.000* 0.000* 0.000* 0.003*
T1 = when the clinical response to ECT treatment was received, T2 = post-ECT treatment, t = Student’s t test. * p < 0.05.
Serum BDNF levels were measured in some studies, while plasma BDNF levels were measured in others. The time of assessment of neurotrophin levels and the clinical scale differed. Likewise, it is believed that differences in the form of ECT application, the anaesthetic substances used, the centrifuge and storage of blood samples in the laboratory, the measurement kits used, etc. may also affect the results. This suggests that there may be differences that arise out of methodological differences between the results of our study and those of other studies. It is envisaged that a more significant increase may be observed in serum BDNF and NGF levels only in studies with a wider sample. The effects of factors such as sex and age on serum BDNF and NGF levels could not be evaluated precisely in our study due to our small sample. Another important point that might have affected the results of studies is that in all studies but one Hu et al. (2010), the patients continued to take antidepressants. As mentioned earlier, antidepressant treatment led to a rise in BDNF levels. Piccinni et al. (2009) reported that the baseline plasma BDNF levels in the remission group were higher when compared to the corresponding levels in the non-remission group. However, in their study, such higher baseline plasma BDNF levels in the remission group may be related with antidepressant treatment. In our study, on the other hand, patients were not given antidepressant treatment. Thus, antidepressant medication had no effect at all in the elevation of BDNF levels. In contrast, the drugs used, such as benzodiazepines and hydroxyzine, may also have some reducing effects on serum BDNF and NGF levels (Huopaniemi et al., 2004; Huang and Hung, 2009). 4.3. Clinical scales and change with ECT After ECT treatment, a statistically significant reduction was detected in the severity of depression (in HAM-D scores). This result is consistent with the findings of other similar studies in the literature (Haghighi et al., 2013; Hu et al., 2010; Okamoto et al., 2008). In the literature, contradictory results have been reported by other similar studies. In some studies, a correlation was not detected consistently with the results of our study (Haghighi et al., 2013; Gedge et al., 2012). On the other hand, other studies have asserted that there exists a positive correlation between the serum and plasma BDNF levels and the recovery of depression symptoms (Piccinni et al., 2009; Hu et al., 2010; Okamoto et al., 2008). Hu et al. (2010) also reported a positive correlation between the increase in serum BDNF levels and the recovery in cognitive dysfunction and retardation sub-groups in the HAM-D scale. 4.4. Limitations of study One of the main limitations of our study was our small sample. However, in comparison to other similar studies, the size of our sample may be the equivalent or larger. But, nevertheless, the significance of a correlation between the more significant increase in serum BDNF and NGF levels after ECT treatment and the reduction in the severity of depression and serum neurotrophin levels requires new studies with larger samples. Furthermore, the size of
our sample is insufficient to assess the effects of such factors as sex and age on serum neurotrophin levels as well. Bus et al. (2011) reported that in addition to sex and age, such factors as smoking and alcohol, the time the blood sample was taken, the time until the sample is processed, how much time after the meal the blood sample was taken, exercise, the menstrual cycle, and the characteristics of the storage environment of the sample are also effective on serum neurotrophin levels (Bus et al., 2011). In our study, the failure to assess the effects of smoking and the menstrual characteristics of female patients, representing the majority of the sample, may be considered a limitation. As discussed in the similar studies, the time needed for the occurrence of a significant increase in neurotrophins such as BDNF and NGF by treatment (antidepressant or ECT treatment) is still unclear. Therefore, in future studies, we believe that more meaningful results may be reached through a longer post-treatment follow-up period. In our study, the failure to separately group the patients according to remission criterion upon the completion of treatment may also be considered a limitation. The negative correlation between the significant increase in serum BDNF and NGF levels reaching the same level with the control group and the severity of depression and serum neurotrophin levels may be demonstrated in the future through studies classifying remission and non-remission patients. Haghighi et al. (2013) reported that the failure to find a relationship between plasma BNDF levels and recovery in the severity of depression may be explained by genetic factors such as BNDF Val66Met gene polymorphism. In our study, the failure to check BDNF gene polymorphisms (particularly Val66Met) may also be considered to be a limitation. The determination of the effects of ECT or antidepressant treatments on neurotrophin levels should be supported by genetic-based studies.
5. Conclusions This study is important because it is the first study conducted in our country to examine the effects of ECT treatment on serum neurotrophin levels. In addition, the examination of NGF levels, which seem to have lost their importance regarding BDNF, is also believed to contribute to the literature. Whether BDNF may be a biological indicator in the diagnosis of major depression and in monitoring the response to treatment is still a matter of debate among researchers. The fact that in major depression, BDNF is lower than in healthy volunteers and rises with treatment, while this rise is not observed in patients who do not respond to treatment, makes BDNF an indicator. However, it is affected by many stress-related psychological and medical disorders, reducing the specificity of BDNF for major depression. A review of the findings obtained so far reveals that it is difficult to declare that BDNF and NGF are specific indicators for major depression. In the future, studies assessing the neurotrophic factors together with neuro-endocrinologic and genetic processes may help to elucidate psycho-biological characteristics of psychological disorders, particularly major depression.
A.E. Bilgen et al. / Brain Research Bulletin 104 (2014) 82–87
Disclosure The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. References Angelucci, F., Aloe, L., Vasquez, P.J., Mathe, A.A., 2000. Mapping the differences in the brain concentration of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in an animal model of depression. Neuroreport 27, 1369–1373. Angelucci, F., Aloe, L., Jimenez-Vasquez, P., Mathe, A.A., 2003. Electroconvulsive stimuli alter nerve growth factor but not brain-derived neurotrophic factor concentrations in brains of a rat model of depression. Neuropeptides 37, 51–56. Aydemir, O., Deveci, A., Taneli, F., 2005. The effect of chronic antidepressant treatment on serum brain-derived neurotrophic factor levels in depressed patients: a preliminary study. Prog. Neuropsychopharmacol. Biol. Psychiatry 29, 261–265. Bocchio-Chiavetto, L., Bagnardi, V., Zanardini, R., Molteni, R., Nielsen, M.G., Placentino, A., 2010. Serum and plasma BDNF levels in major depression: a replication study and meta-analyses. World J. Biol. Psychiatry 11, 763–773. Bocchio-Chiavetto, L., Zanardini, R., Bortolomasi, M., Abate, M., Segala, M., Giacopuzzi, M., 2006. Electroconvulsive Therapy (ECT) increases serum brain derived neurotrophic factor (BDNF) in drug resistant depressed patients. Eur. Neuropsychopharmacol. 16, 620–624. Bus, B.A., Molendijk, M.L., Penninx, B.J., Buitelaar, J.K., Kenis, G., Prickaerts, J., 2011. Determinants of serum brain-derived neurotrophic factor. Psychoneuroendocrinology 36, 228–239. Brunoni, A.R., Lopes, M., Frengi, 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. Int. J. Neuropsychopharmacol. 11, 1169–1180. Carvey, P.M., 1998. Drug Action in the Central Nervous System. Oxford University, New York, pp. 123–150. Fernandes, B., Gama, C.S., Massuda, R., Torres, M., Camargo, D., Kunz, 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. Neurosci. Lett. 453, 195–198. 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. Front. Psychiatry 12. Gönül, A.S., Akdeniz, F., Taneli, F., Donat, O., Eker, C., Vahip, S., 2005. Effect of treatment on serum brain-derived neurotrophic factor levels in depressed patients. Eur. Arch. Psychiatry Clin. Neurosci. 255, 381–386. Grönli, O., Stensland, G.O., Wynn, R., Olstad, R., 2009. Neurotrophic factors in serum following ECT: a pilot study. World J. Biol. Psychiatry 10, 295–301. Hadjiconstantinou, M., Mcguire, L., Duchemin, A.M., Laskowski, B., Kiecolt-Glaser, J., Glaser, R., 2001. Changes in plasma NGF levels in older adults associated with chronic stress. J. Neuroimmunol. 116, 102–106. Haghighi, M., Salehi, I., Erfani, P., Jahangard, L., Bajoghli, H., Holsboer-Trachsler, E., 2013. Additional ECT increases BDNF-levels in patients suffering from major depressive disorders compared to patients treated with citalopram only. J. Psychiatr. Res. 47, 908–915. Hu, Y., Yu, X., Yang, F., Si, T., Wang, W., Tan, Y., 2010. The level of serum brain-derived neurotrophic factor is associated with the therapeutic efficacy of modified electroconvulsive therapy in Chinese patients with depression. J. ECT 26, 121–125.
87
Huang, T.L., Hung, Y.Y., 2009. Lorazepam reduces the serum brain-derived neurotrophic factor level in schizophrenia patients with catatonia. Prog. Neuropsychopharmacol. Biol. Psychiatry 33, 158–159. Huopaniemi, L., Keist, R., Randolph, A., Certa, U., Rudolph, U., 2004. Diazepaminduced adaptive plasticity revealed by ␣1 GABA-A receptor-specific expression profiling. J. Neurochem. 88, 1059–1067. Karege, F., Perret, G., Bondolfi, G., Schwald, M., Bertschy, G., Aubry, J.M., 2002a. Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res. 109, 143–148. Karege, F., Schwald, M., Cisse, M., 2002b. Postnatal developmental profile of brainderived neurotrophic factor in rat brain and platelets. Neurosci. Lett. 328, 261–264. Kim, J., Gale, K., Kondratyev, A., 2010. Effects of repeated minimal electroshock seizures on NGF, BDNF and FGF-2 protein in the rat brain during postnatal development. Int. J. Dev. Neurosci. 28, 227–232. Kotan, Z., Sarandöl, A., Saygın, E.S., Akkaya, C., 2009. Depression, neuroplasticity and neurotrophic factors. Curr. Approach. Psychiatry 1, 22–35. Lee, J., Duan, W., Mattson, M.P., 2002. Evidence that brain-derived neuro-trophic factor is required for basal neurogenesis and mediates in part the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J. Neurochem. 82, 1367–1375. Martino, M., Rocchi, G., Escelsior, A., Contini, P., Colicchio, S., de Berardis, D., 2013. NGF serum levels variations in major depressed patients receiving duloxetine. Psychoneuroendocrinology 13, 47–54. Murray, C.J., Lopez, A.D., 1997. Alternative projections of mortality and disability by cause 1990–2020. Global Burden of Disease Study. Lancet 349, 1498–1504. Nierenberg, A.A., Amsterdam, J.D., 1990. Treatment-resistant depression: definition and treatment approaches. J. Clin. Psychiatry 51, 39–47, discussion 48–50. Okamoto, T., Yoshimura, R., Ikenouchi-Sugita, A., Hori, H., Umene-Nakano, W., Inoue, Y., 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. Prog. Neuropsychopharmacol. Biol. Psychiatry 32, 1185–1190. Piccinni, A., Del Debbio, A., Medda, P., Bianchi, C., Roncaglia, I., Veltri, A., 2009. Plasma Brain-Derived Neurotrophic Factor in treatment-resistant depressed patients receiving ECT. Eur. Neuropsychopharmacol. 19, 349–355. Reus, G.Z., Stringari, R.B., Ribeiro, K.F., Cipriano, A.L., Panizzutti, B.S., Stertz, L., 2011. Maternal deprivation induces depressive-like behaviour and alters neurotrophin levels in the rat brain. Eurochem. Res. 36, 460–466. Sala, M., Perez, J., Soloff, P., Ucelli di Nemi, S., Caverzasi, E., Soares, J.C., 2004. Stress and hippocampal abnormalities in psychiatric disorders. Eur. Neuropsychopharmacol. 14, 393–405. Schulte-Herbruggen, O., Fuchs, E., Abumaria, N., Ziegler, A., Danker-Hopfe, H., Hiemke, C., 2009. Effects of escitalopram on the regulation of brain-derived neurotrophic factor and nerve growth factor protein levels in a rat model of chronic stress. J. Neurosci. Res. 87, 2551–2560. Shirayama, Y., Chen, A.C., Nakagawa, S., Russell, D.S., Duman, R.S., 2002. Brainderived neurotrophic factor produces antidepressant effects in behavioral models of depression. J. Neurosci. 22, 3251–3261. Stahl, S.M., (T. Uzbay, Trans.) 2012. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications, 3rd ed. Istanbul Medical Publishing. Xiong, P., Zeng, Y., Wan, J., Xiaohan, D.H., Tan, D., Lu, J., 2011. The role of NGF and IL-2 serum level in assisting the diagnosis in first episode schizophrenia. Psychiatry Res. 189, 72–76. Yulu˘g, B., Ozan, E., Gönül, A.S., Kilic¸, E., 2009. Brain derived neurotrophic factor, stress and depression: a minireview. Brain Res. Bull. 78, 267–269.
