The World Journal of Biological Psychiatry, 2015; 16: 135–138
BRIEF REPORT
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Brain-derived neurotrophic factor and subcallosal deep brain stimulation for refractory depression
RAJAMANNAR RAMASUBBU1,2,3,4, HALEY A. VECCHIARELLI3,4,6, MATTHEW N. HILL1,3,4,5 & ZELMA H.T. KISS2,4 1Departments
of Psychiatry, University of Calgary, Calgary, AB, Canada, 2Department of Clinical Neuroscience, University of Calgary, AB, Canada, 3Mathison Centre for Mental Health Research and Education, University of Calgary, AB, Canada, 4Hotchkiss Brain Institute, University of Calgary, AB, Canada, 5Department of Cell Biology and Anatomy, University of Calgary, AB, Canada, and 6Department of Neuroscience, University of Calgary, AB, Canada
Abstract Objectives. Subcallosal cingulate (SCC) deep brain stimulation (DBS) is a promising experimental treatment for treatmentresistant depression (TRD). Given the role of brain-derived neurotrophic factor (BDNF) in neuroplasticity and antidepressant efficacy, we examined the effect of SCC-DBS on serum BDNF in TRD. Methods. Four patients with TRD underwent SCC-DBS treatment. Following a double-blind stimulus optimization phase of 3 months, patients received continuous stimulation in an open label fashion for 6 months. Clinical improvement in depressive symptoms was evaluated bi-weekly for 6 months using the Hamilton Depression Rating Scale (HDRS). Mature serum BDNF levels were measured before and 9–12 months after surgery. Results. Three patients responded to SCC-DBS: two showed full clinical response (50% reduction in HDRS scores) and one had partial response (35% reduction in HDRS scores) at the clinical endpoint. Interestingly, all four patients showed reduction in serum BDNF concentration from pre-DBS baseline. Conclusions. SCC-DBS for TRD may be associated with decreased levels of serum BDNF. Longitudinal studies with multiple measurements in a larger sample are required to determine the role of BDNF as a biomarker of SCC-DBS antidepressant efficacy. Key words: brain-derived neurotrophic factor, depression, deep brain stimulation, subcallosal cingulate region, biomarker
Introduction Despite adequate treatment, 10–20% of patients with depression will develop treatment-resistant depression (TRD) (Fava 2003). Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) has emerged as a treatment option for TRD. Five openlabel studies involving 72 patients have been published, and DBS showed benefit and safety (Lozano et al. 2008; Puigdemont et al. 2011; Holtzheimer et al. 2012; Lozano et al. 2012; Ramasubbu et al. 2013). Although these results are encouraging, approximately 40–50% of patients failed to respond and 70–80% failed to achieve clinical remission with SCC-DBS in the first 2 years of treatment. Furthermore an industry-sponsored sham-controlled randomized and blinded trial was recently terminated
early (http://www.sjm.com/broaden). One of the key reasons for DBS failure is the lack of evidence-based biomarkers of response to select the right patients for this treatment. Another related issue is that the basic mechanisms underlying the antidepressant effects of SCC-DBS remains unknown, which limits our understanding of why some patients fail to respond to SCC-DBS. Among the neurochemical substrates implicated in antidepressant therapies, brain-derived neurotrophic factor (BDNF) has been extensively investigated. BDNF has been implicated in the pathophysiology of major depressive disorder (MDD) as well as in the therapeutic mechanisms of antidepressant treatment (Schmidt and Duman 2010). BDNF levels are generally reduced in patients with depression compared to
Correspondence: Dr Rajamannar Ramasubbu, Department of Psychiatry and Clinical Neurosciences, University of Calgary, Mathison Centre for Mental Health Research and Education, TRW building, Room 4D64, 3280 Hospital Drive NW, Calgary, Alberta, Canada T2N 4Z6. Tel: ⫹ 1-403-210-6890. Fax: ⫹ 1-403-210-9114. E-mail: [email protected] (Received 24 March 2014 ; accepted 4 August 2014 ) ISSN 1562-2975 print/ISSN 1814-1412 online © 2014 Informa Healthcare DOI: 10.3109/15622975.2014.952775
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controls and elevated in response to selective serotonin reuptake inhibitors (SSRI) medication and electroconvulsive treatment (ECT) (Brunoni et al. 2008; Sen et al. 2008; Molendijk et al. 2011). Accordingly, these studies suggest that reduced serum BDNF could be reflective of deficient central BDNF and function as a peripheral biomarker of MDD; following this logic, increased circulating BDNF levels may be a surrogate marker of antidepressant response. In rodent models of DBS, hippocampal BDNF is increased following stimulation of ventromedial prefrontal cortex, which is homologous to SCC in human (Hamani et al. 2012). Given the relative consistency of BDNF changes in depression, and their alteration by antidepressant regiments, it seems reasonable to predict that elevations in BDNF levels would be expected in humans following SCC-DBS as well. To explore this hypothesis we examined serum BDNF in 4 patients with TRD who participated in a pilot SCC-DBS study, both prior to and following treatment intervention (Ramasubbu et al. 2013).
before DBS surgery (pre-DBS) and 9–12 months after stimulation was initiated (post-DBS). Among four patients, post-DBS blood sample for one patient (patient #4) was collected at 12 months because she was away. Samples were collected in anticoagulantfree tubes and allowed to clot at room temperature for 30 min followed by centrifugation at 1000 rpm for 15 min at room temperature. Serum samples were stored at ⫺78°C, but underwent one freeze– thaw cycle prior to analysis. Mature BDNF was measured in serum using a commercial ELISA kit (BDNF Emax ImmunoAssay System, Promega) according to the manufacturer’s instructions. Briefly, 96-well plates were coated overnight with an antiBDNF monoclonal antibody. The next day, after a blocking step, plates were incubated with samples and standards, followed by incubation with an antihuman BDNF polyclonal antibody, followed by incubation with an anti-IgY horse radish peroxidase conjugate. Plates were analysed using a SpectraMax 190 (Molecular Devices) using SoftMax Pro 6.1 software (Molecular Devices) at an absorbance of 450 nm. Fifty μl of serum were run in triplicate and compared to the standard curve, to determine absolute BDNF levels.
Methods Patient selection, evaluation, DBS surgery, programming optimization, and outcomes have been previously described in detail (Ramasubbu et al. 2013). In brief, the study was approved by the University of Calgary research ethics board. Four patients who met the criteria for MDD using structured clinical interview, and severe depression, defined as minimum score of 20 out of 52, on the 17-item Hamilton Depression Rating Scale (HDRS; Hamilton 1960) were enrolled. All were treatment resistant as determined by failure to respond to four different classes of antidepressants, evidence-based psychotherapy or electroconvulsive treatment despite adequate dosage, duration and compliance with treatment (Thase and Rush 1997; Sackeim et al. 2001; Fava 2003). DBS electrodes (3387, Medtronic, Minneapolis, MN) were implanted bilaterally spanning the grey–white–grey matter of the SCC gyrus, and connected to the implantable pulse generator (Kinetra, Medtronic, Minneapolis, MN). The first 3 months after DBS implantation, stimulus parameters were adjusted to determine optimal response. For the subsequent 6 months, all patients received open-label continuous stimulation using their optimal stimulus parameters. Clinical efficacy was evaluated every 2 weeks using HDRS-17 and the secondary measures outlined in Ramasubbu et al. (2013). Serum BDNF measures were obtained using 10 ml of venous blood, drawn within the 6 weeks
Results Clinical, demographic, stimulation characteristics of each patient including pre- and post-HDRS scores and BDNF levels are shown in Table I. Three patients responded with patient 1 achieving 35% reduction in HDRS from baseline, and patients 2 and 3 a 50% improvement. Patient 4 did not respond. Serum BDNF levels decreased in all four patients resulting in a significant change of 13.20 (⫾ 2.73, SD) ng/ml before to 11.64 (⫾ 3.13) ng/ml after DBS (paired t-test, t(3) ⫽ 7.14, P ⬍ 0.01). Correlation between percent reduction in BDNF and HDRS was not significant (r ⫽ 0.20, P ⫽ 0.80). There were no surgeryor stimulation-related side effects at the clinical end point of the study.
Discussion This is the first report on changes in serum BDNF concentration related to SCC-DBS for TRD. Contrary to animal data and human responses to pharmacological treatments of depression, we found decreases in serum BDNF levels after SCC-DBS in all four patients. Because of the small sample size, this must be considered preliminary and requires further investigation. The direction of serum BDNF concentration change as a surrogate marker of clinical response to
BDNF and SCC-DBS 137 Table I. Patients’ characteristics, stimulation parameters, medications and serum BDNF concentration. Characteristics
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Age Gender Medications during SCC-DBS
Stimulation parameters* Electrode contacts** Pre-DBS HDRS Post-DBS HDRS Responder Status Pre-DBS BDNF Post-DBS BDNF
Patient 1
Patient 2
Patient 3
Patient 4
49 Female Citalopram 60 mg/day
56 Female Duloxetine 60 mg/day
46 Male No antidepressants
50 Female Dexedrine XR 10 mg/day
Clonazepam 0.5 mg QHS
Zopiclone 22.5 mg QHS
Vitamin D 4000 iu ⫹ calcium Sporadic testosterone im
Risperidone 0.75 mg QHS
Lithium carbonate 600mg QHS Gabapentin 1200 mg/day Quetiapine 150 mg QHS Clonazepam 1.5 mg/day Multivitamins Synthyroid 0.15 mg/day 130 Hz/150 μs/3 V 130 Hz/210 μs/3 V 130 Hz/450 μs/2 V
Mirtazepine 11.25 mg QHS
C ⫹ 2–
C ⫹ 3–
C ⫹ 0–
C ⫹ 2–/3–
C ⫹ 5– 33 23 Partial Responder 9.24 ng/ml 7.13 ng/ml
C ⫹ 4– 30 15 Responder 13.74 ng/ml 12.05 ng/ml
C ⫹ 4–/5– 33 16 Responder 15.44 ng/ml 14.18 ng/ml
C ⫹ 4–/5– 27 25 Non-responder 14.37 ng/ml 13.21 ng/ml
Aripiprazole 6 mg QHS 130 Hz/90 μs/5 V
*Frequency is reported in Hertz (Hz), pulse width in microseconds (μs), and amplitude in voltage (V). Stimulation type was monopolar. **0–3 left, 4–7 right brain, 3 and 7 are most dorsal, 0 and 4 are most ventral. C⫹ neurostimulator case as anode and – electrode contact as cathode. Stimulation parameters reported are from post-optimization phase (open label).
antidepressant therapies is inconsistent. Some studies showed increase in BDNF with non-invasive brain stimulation such as ECT and repetitive transcranial magnetic stimulation (rTMS) (Zanardini et al. 2006; Marano et al. 2007; Okamoto et al. 2008), while others have not replicated these findings (Fernandes et al. 2009; Gedge et al. 2012). The literature on antidepressant treatment and BDNF concentration showed class specific significant associations between increase in BDNF and SSRI treatment, whereas this association was not significant with other antidepressants such as mirtazepine and serotonin-norepinephrine reuptake inhibitors (Molendijk et al. 2011). These previous findings and our results suggest that increases in serum BDNF concentrations following antidepressant treatment may be specific to the mode of intervention, per se, and not a broad surrogate biomarker of treatment response. There are several possible reasons for a decrease in serum BDNF concentration in our patients. First, our patients were highly refractory having tried multiple medications in the past, and three were taking longterm antidepressants for years. This may have resulted in a higher than normal serum BDNF at baseline in these patients. We did not allow changes in antidepressants or other psychotropic medications during the DBS trial and therefore the effect of concurrent medications on changes in BDNF levels would be negligible. However, at present, the interactive effects of DBS and psychotropic medications on serum BDNF
levels remain unknown. Although the possibility exists, the discontinuation of antidepressants or psychotropic medications or poor compliance following DBS seems unlikely to account for decreases in serum BDNF as to our knowledge, patients were compliant with their usual medications during our study period. Another important aspect to be addressed is whether the active contacts used for chronic stimulation have influenced our results. In all four patients, the active contacts for stimulation were ventral (4 and 5) in the right side and in three patients they were dorsal (2 and 3) in the left side (refer Table I). The ventral contracts by proximity may stimulate uncinate fasciculus the fibre tracts which connect SCC with hippocampus and amygdala. Taking into account that BDNF is highly expressed in the hippocampus and hippocampal BDNF is increased following stimulation of ventromedial prefrontal cortex in rodent models of DBS (Hamani et al. 2012), it is possible that unilateral stimulation of uncinate fasciculus could be insufficient to induce optimal secretion of BDNF in our patients. The proposition that bilateral continuous stimulation of uncinate fasciculus may enhance BDNF expression in hippocampus and also in serum needs further evaluation. Third, it is possible that a relatively early rise in BDNF may have occurred following the onset of DBS treatment, which then subsided and declined over time. This hypothesis is consistent with a case report of DBS within the habenula where BDNF levels increased initially and then declined
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over time (Hoyer et al. 2012). Thorough temporal mapping of changes in BDNF following SCC-DBS is required to understand if earlier changes were missed in our analysis. In addition to sample size, it is also possible that the long-term storage and freeze–thaw cycle which all of the samples underwent may have influenced protein levels of BDNF; however, the values we report are consistent with previous studies in human samples, and all of the samples were similarly exposed to the same freeze–thaw, arguing against this as a possibility to explain the difference in pre- and post-DBS BDNF levels. The decline in serum BDNF concentration after long-term storage at –80°C will be negligible. In summary, the current data do not support the hypothesis that increase in circulating levels of BDNF may represent a biomarker of treatment response to SCC-DBS. Longitudinal studies over multiple time points and involving larger sample size are needed to determine the role of BDNF as a biomarker of SCCDBS for TRD response. Further research is required to determine the significance of circulating BDNF for clinical staging of depression (e.g. chronicity or refractoriness) and the specificity of this biomarker to different treatment modalities or brain targets.
Acknowledgements This study was supported by grants from the Hotchkiss Brain Institute (HBI) Clinical Research Unit, University of Calgary, and Alberta Innovates Health Solutions. We thank Dr G. MacQueen for screening patients, Susan Anderson for stimulus programming, and Ana Andreazza her assistance in analysis of the samples.
Statement of Interest None to declare.
References Brunoni AR, 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. Int J Neuropsychopharmacol 11(8):1169–1180. Fava M. 2003. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry 53:649–659. Fernandes B, Gama CS, Massuda R, Torres M, Camargo D, Kunz M, et al. 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 3:12. Hamani C, Machado DC, Hipolide DC, Dubiela FP, Suchecki D, Macedo CE, et al. 2012. Deep brain stimulation reverses anhedonic-like behavior in a chronic model of depression: role of serotonin and brain derived neurotrophic factor. Biol Psychiatry 71:30–35. Hamilton M. 1960. A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62. Holtzheimer PE, Kelley ME, Gross RE, Filkowski MM, Garlow SJ, Barrocas A, et al. 2012. Subcallosal cingulate deep brain stimulation for treatment-resistant unipolar and bipolar depression. Arch Gen Psychiatry 69:150–158. Hoyer C, Kranaster L, Sartorius A, Hellweg R, Gass P. 2012. Long-term course of brain-derived neurotrophic factor serum levels in a patient treated with deep brain stimulation of the lateral habenula. Neuropsychobiology 65:147–152. Lozano AM, Giacobbe P, Hamani C, Rizvi SJ, Kennedy SH, Kolivakis TT, et al. 2012. A multicenter pilot study of subcallosal cingulate area deep brain stimulation for treatmentresistant depression. J Neurosurg 116:315–322. Lozano AM, Mayberg HS, Giacobbe P, Hamani C, Craddock RC, Kennedy SH. 2008. Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. Biol Psychiatry 64:461–467. Marano CM, Phatak P, Vemulapalli UR, Sasan A, Nalbandyan MR, Ramanujam S, et al. 2007. Increased plasma concentration of brain-derived neurotrophic factor with electroconvulsive therapy: a pilot study in patients with major depression. J Clin Psychiatry 68:512–517. Molendijk ML, Bus BA, Spinhoven P, Penninx BW, Kenis G, Prickaerts J, et al. 2011. Serum levels of brain-derived neurotrophic factor in major depressive disorder: state-trait issues, clinical features and pharmacological treatment. Mol Psychiatry 16:1088–1095. Okamoto T, Yoshimura R, Ikenouchi-Sugita A, Hori H, Umene-Nakano W, Inoue Y, et al. 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. Puigdemont D, Perez-Egea R, Portella MJ, Molet J, de Diego-Adelino J, Gironell A, et al. 2011. Deep brain stimulation of the subcallosal cingulate gyrus: further evidence in treatment-resistant major depression. Int J Neuropsychopharmacol 1–13. Ramasubbu R, Anderson S, Haffenden A, Chavda S, Kiss ZH. 2013. Double-blind optimization of subcallosal cingulate deep brain stimulation for treatment-resistant depression: a pilot study. J Psychiatry Neurosci 38:120160. Sackeim HA, Rush AJ, George MS, Marangell LB, Husain MM, Nahas Z, et al. 2001. Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome. Neuropsychopharmacology 25:713–728. Schmidt HD, Duman RS. 2010. Peripheral BDNF produces antidepressant-like effects in cellular and behavioral models. Neuropsychopharmacology 35:2378–2391. Sen S, Duman R, Sanacora G. 2008. Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biol Psychiatry 64(6):527–532. Thase ME, Rush AJ. 1997. When at first you don’t succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry 58(Suppl 13):23–29. Zanardini R, Gazzoli A, Ventriglia M, Perez J, Bignotti S, Rossini PM, et al. 2006. Effect of repetitive transcranial magnetic stimulation on serum brain derived neurotrophic factor in drug resistant depressed patients. J Affect Disord 91:83–86.
BRIEF REPORT
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Brain-derived neurotrophic factor and subcallosal deep brain stimulation for refractory depression
RAJAMANNAR RAMASUBBU1,2,3,4, HALEY A. VECCHIARELLI3,4,6, MATTHEW N. HILL1,3,4,5 & ZELMA H.T. KISS2,4 1Departments
of Psychiatry, University of Calgary, Calgary, AB, Canada, 2Department of Clinical Neuroscience, University of Calgary, AB, Canada, 3Mathison Centre for Mental Health Research and Education, University of Calgary, AB, Canada, 4Hotchkiss Brain Institute, University of Calgary, AB, Canada, 5Department of Cell Biology and Anatomy, University of Calgary, AB, Canada, and 6Department of Neuroscience, University of Calgary, AB, Canada
Abstract Objectives. Subcallosal cingulate (SCC) deep brain stimulation (DBS) is a promising experimental treatment for treatmentresistant depression (TRD). Given the role of brain-derived neurotrophic factor (BDNF) in neuroplasticity and antidepressant efficacy, we examined the effect of SCC-DBS on serum BDNF in TRD. Methods. Four patients with TRD underwent SCC-DBS treatment. Following a double-blind stimulus optimization phase of 3 months, patients received continuous stimulation in an open label fashion for 6 months. Clinical improvement in depressive symptoms was evaluated bi-weekly for 6 months using the Hamilton Depression Rating Scale (HDRS). Mature serum BDNF levels were measured before and 9–12 months after surgery. Results. Three patients responded to SCC-DBS: two showed full clinical response (50% reduction in HDRS scores) and one had partial response (35% reduction in HDRS scores) at the clinical endpoint. Interestingly, all four patients showed reduction in serum BDNF concentration from pre-DBS baseline. Conclusions. SCC-DBS for TRD may be associated with decreased levels of serum BDNF. Longitudinal studies with multiple measurements in a larger sample are required to determine the role of BDNF as a biomarker of SCC-DBS antidepressant efficacy. Key words: brain-derived neurotrophic factor, depression, deep brain stimulation, subcallosal cingulate region, biomarker
Introduction Despite adequate treatment, 10–20% of patients with depression will develop treatment-resistant depression (TRD) (Fava 2003). Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) has emerged as a treatment option for TRD. Five openlabel studies involving 72 patients have been published, and DBS showed benefit and safety (Lozano et al. 2008; Puigdemont et al. 2011; Holtzheimer et al. 2012; Lozano et al. 2012; Ramasubbu et al. 2013). Although these results are encouraging, approximately 40–50% of patients failed to respond and 70–80% failed to achieve clinical remission with SCC-DBS in the first 2 years of treatment. Furthermore an industry-sponsored sham-controlled randomized and blinded trial was recently terminated
early (http://www.sjm.com/broaden). One of the key reasons for DBS failure is the lack of evidence-based biomarkers of response to select the right patients for this treatment. Another related issue is that the basic mechanisms underlying the antidepressant effects of SCC-DBS remains unknown, which limits our understanding of why some patients fail to respond to SCC-DBS. Among the neurochemical substrates implicated in antidepressant therapies, brain-derived neurotrophic factor (BDNF) has been extensively investigated. BDNF has been implicated in the pathophysiology of major depressive disorder (MDD) as well as in the therapeutic mechanisms of antidepressant treatment (Schmidt and Duman 2010). BDNF levels are generally reduced in patients with depression compared to
Correspondence: Dr Rajamannar Ramasubbu, Department of Psychiatry and Clinical Neurosciences, University of Calgary, Mathison Centre for Mental Health Research and Education, TRW building, Room 4D64, 3280 Hospital Drive NW, Calgary, Alberta, Canada T2N 4Z6. Tel: ⫹ 1-403-210-6890. Fax: ⫹ 1-403-210-9114. E-mail: [email protected] (Received 24 March 2014 ; accepted 4 August 2014 ) ISSN 1562-2975 print/ISSN 1814-1412 online © 2014 Informa Healthcare DOI: 10.3109/15622975.2014.952775
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controls and elevated in response to selective serotonin reuptake inhibitors (SSRI) medication and electroconvulsive treatment (ECT) (Brunoni et al. 2008; Sen et al. 2008; Molendijk et al. 2011). Accordingly, these studies suggest that reduced serum BDNF could be reflective of deficient central BDNF and function as a peripheral biomarker of MDD; following this logic, increased circulating BDNF levels may be a surrogate marker of antidepressant response. In rodent models of DBS, hippocampal BDNF is increased following stimulation of ventromedial prefrontal cortex, which is homologous to SCC in human (Hamani et al. 2012). Given the relative consistency of BDNF changes in depression, and their alteration by antidepressant regiments, it seems reasonable to predict that elevations in BDNF levels would be expected in humans following SCC-DBS as well. To explore this hypothesis we examined serum BDNF in 4 patients with TRD who participated in a pilot SCC-DBS study, both prior to and following treatment intervention (Ramasubbu et al. 2013).
before DBS surgery (pre-DBS) and 9–12 months after stimulation was initiated (post-DBS). Among four patients, post-DBS blood sample for one patient (patient #4) was collected at 12 months because she was away. Samples were collected in anticoagulantfree tubes and allowed to clot at room temperature for 30 min followed by centrifugation at 1000 rpm for 15 min at room temperature. Serum samples were stored at ⫺78°C, but underwent one freeze– thaw cycle prior to analysis. Mature BDNF was measured in serum using a commercial ELISA kit (BDNF Emax ImmunoAssay System, Promega) according to the manufacturer’s instructions. Briefly, 96-well plates were coated overnight with an antiBDNF monoclonal antibody. The next day, after a blocking step, plates were incubated with samples and standards, followed by incubation with an antihuman BDNF polyclonal antibody, followed by incubation with an anti-IgY horse radish peroxidase conjugate. Plates were analysed using a SpectraMax 190 (Molecular Devices) using SoftMax Pro 6.1 software (Molecular Devices) at an absorbance of 450 nm. Fifty μl of serum were run in triplicate and compared to the standard curve, to determine absolute BDNF levels.
Methods Patient selection, evaluation, DBS surgery, programming optimization, and outcomes have been previously described in detail (Ramasubbu et al. 2013). In brief, the study was approved by the University of Calgary research ethics board. Four patients who met the criteria for MDD using structured clinical interview, and severe depression, defined as minimum score of 20 out of 52, on the 17-item Hamilton Depression Rating Scale (HDRS; Hamilton 1960) were enrolled. All were treatment resistant as determined by failure to respond to four different classes of antidepressants, evidence-based psychotherapy or electroconvulsive treatment despite adequate dosage, duration and compliance with treatment (Thase and Rush 1997; Sackeim et al. 2001; Fava 2003). DBS electrodes (3387, Medtronic, Minneapolis, MN) were implanted bilaterally spanning the grey–white–grey matter of the SCC gyrus, and connected to the implantable pulse generator (Kinetra, Medtronic, Minneapolis, MN). The first 3 months after DBS implantation, stimulus parameters were adjusted to determine optimal response. For the subsequent 6 months, all patients received open-label continuous stimulation using their optimal stimulus parameters. Clinical efficacy was evaluated every 2 weeks using HDRS-17 and the secondary measures outlined in Ramasubbu et al. (2013). Serum BDNF measures were obtained using 10 ml of venous blood, drawn within the 6 weeks
Results Clinical, demographic, stimulation characteristics of each patient including pre- and post-HDRS scores and BDNF levels are shown in Table I. Three patients responded with patient 1 achieving 35% reduction in HDRS from baseline, and patients 2 and 3 a 50% improvement. Patient 4 did not respond. Serum BDNF levels decreased in all four patients resulting in a significant change of 13.20 (⫾ 2.73, SD) ng/ml before to 11.64 (⫾ 3.13) ng/ml after DBS (paired t-test, t(3) ⫽ 7.14, P ⬍ 0.01). Correlation between percent reduction in BDNF and HDRS was not significant (r ⫽ 0.20, P ⫽ 0.80). There were no surgeryor stimulation-related side effects at the clinical end point of the study.
Discussion This is the first report on changes in serum BDNF concentration related to SCC-DBS for TRD. Contrary to animal data and human responses to pharmacological treatments of depression, we found decreases in serum BDNF levels after SCC-DBS in all four patients. Because of the small sample size, this must be considered preliminary and requires further investigation. The direction of serum BDNF concentration change as a surrogate marker of clinical response to
BDNF and SCC-DBS 137 Table I. Patients’ characteristics, stimulation parameters, medications and serum BDNF concentration. Characteristics
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Age Gender Medications during SCC-DBS
Stimulation parameters* Electrode contacts** Pre-DBS HDRS Post-DBS HDRS Responder Status Pre-DBS BDNF Post-DBS BDNF
Patient 1
Patient 2
Patient 3
Patient 4
49 Female Citalopram 60 mg/day
56 Female Duloxetine 60 mg/day
46 Male No antidepressants
50 Female Dexedrine XR 10 mg/day
Clonazepam 0.5 mg QHS
Zopiclone 22.5 mg QHS
Vitamin D 4000 iu ⫹ calcium Sporadic testosterone im
Risperidone 0.75 mg QHS
Lithium carbonate 600mg QHS Gabapentin 1200 mg/day Quetiapine 150 mg QHS Clonazepam 1.5 mg/day Multivitamins Synthyroid 0.15 mg/day 130 Hz/150 μs/3 V 130 Hz/210 μs/3 V 130 Hz/450 μs/2 V
Mirtazepine 11.25 mg QHS
C ⫹ 2–
C ⫹ 3–
C ⫹ 0–
C ⫹ 2–/3–
C ⫹ 5– 33 23 Partial Responder 9.24 ng/ml 7.13 ng/ml
C ⫹ 4– 30 15 Responder 13.74 ng/ml 12.05 ng/ml
C ⫹ 4–/5– 33 16 Responder 15.44 ng/ml 14.18 ng/ml
C ⫹ 4–/5– 27 25 Non-responder 14.37 ng/ml 13.21 ng/ml
Aripiprazole 6 mg QHS 130 Hz/90 μs/5 V
*Frequency is reported in Hertz (Hz), pulse width in microseconds (μs), and amplitude in voltage (V). Stimulation type was monopolar. **0–3 left, 4–7 right brain, 3 and 7 are most dorsal, 0 and 4 are most ventral. C⫹ neurostimulator case as anode and – electrode contact as cathode. Stimulation parameters reported are from post-optimization phase (open label).
antidepressant therapies is inconsistent. Some studies showed increase in BDNF with non-invasive brain stimulation such as ECT and repetitive transcranial magnetic stimulation (rTMS) (Zanardini et al. 2006; Marano et al. 2007; Okamoto et al. 2008), while others have not replicated these findings (Fernandes et al. 2009; Gedge et al. 2012). The literature on antidepressant treatment and BDNF concentration showed class specific significant associations between increase in BDNF and SSRI treatment, whereas this association was not significant with other antidepressants such as mirtazepine and serotonin-norepinephrine reuptake inhibitors (Molendijk et al. 2011). These previous findings and our results suggest that increases in serum BDNF concentrations following antidepressant treatment may be specific to the mode of intervention, per se, and not a broad surrogate biomarker of treatment response. There are several possible reasons for a decrease in serum BDNF concentration in our patients. First, our patients were highly refractory having tried multiple medications in the past, and three were taking longterm antidepressants for years. This may have resulted in a higher than normal serum BDNF at baseline in these patients. We did not allow changes in antidepressants or other psychotropic medications during the DBS trial and therefore the effect of concurrent medications on changes in BDNF levels would be negligible. However, at present, the interactive effects of DBS and psychotropic medications on serum BDNF
levels remain unknown. Although the possibility exists, the discontinuation of antidepressants or psychotropic medications or poor compliance following DBS seems unlikely to account for decreases in serum BDNF as to our knowledge, patients were compliant with their usual medications during our study period. Another important aspect to be addressed is whether the active contacts used for chronic stimulation have influenced our results. In all four patients, the active contacts for stimulation were ventral (4 and 5) in the right side and in three patients they were dorsal (2 and 3) in the left side (refer Table I). The ventral contracts by proximity may stimulate uncinate fasciculus the fibre tracts which connect SCC with hippocampus and amygdala. Taking into account that BDNF is highly expressed in the hippocampus and hippocampal BDNF is increased following stimulation of ventromedial prefrontal cortex in rodent models of DBS (Hamani et al. 2012), it is possible that unilateral stimulation of uncinate fasciculus could be insufficient to induce optimal secretion of BDNF in our patients. The proposition that bilateral continuous stimulation of uncinate fasciculus may enhance BDNF expression in hippocampus and also in serum needs further evaluation. Third, it is possible that a relatively early rise in BDNF may have occurred following the onset of DBS treatment, which then subsided and declined over time. This hypothesis is consistent with a case report of DBS within the habenula where BDNF levels increased initially and then declined
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over time (Hoyer et al. 2012). Thorough temporal mapping of changes in BDNF following SCC-DBS is required to understand if earlier changes were missed in our analysis. In addition to sample size, it is also possible that the long-term storage and freeze–thaw cycle which all of the samples underwent may have influenced protein levels of BDNF; however, the values we report are consistent with previous studies in human samples, and all of the samples were similarly exposed to the same freeze–thaw, arguing against this as a possibility to explain the difference in pre- and post-DBS BDNF levels. The decline in serum BDNF concentration after long-term storage at –80°C will be negligible. In summary, the current data do not support the hypothesis that increase in circulating levels of BDNF may represent a biomarker of treatment response to SCC-DBS. Longitudinal studies over multiple time points and involving larger sample size are needed to determine the role of BDNF as a biomarker of SCCDBS for TRD response. Further research is required to determine the significance of circulating BDNF for clinical staging of depression (e.g. chronicity or refractoriness) and the specificity of this biomarker to different treatment modalities or brain targets.
Acknowledgements This study was supported by grants from the Hotchkiss Brain Institute (HBI) Clinical Research Unit, University of Calgary, and Alberta Innovates Health Solutions. We thank Dr G. MacQueen for screening patients, Susan Anderson for stimulus programming, and Ana Andreazza her assistance in analysis of the samples.
Statement of Interest None to declare.
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