- Email: [email protected]
Transcutaneous Vagus Nerve Stimulation (taVNS) for Major Depressive Disorder: An Open Label Proof-of-Concept Trial
Accepted Manuscript Title: Transcutaneous Vagus Nerve Stimulation (taVNS) for Major Depressive Disorder: an Open Label Proof-of-Concept Trial Author: Alisson Paulino Trevizol, Pedro Shiozawa, Ivan Taiar, Amanda Soares, July Silveira Gomes, Mirna Duarte Barros, Bianca Maria Liquidato, Quirino Cordeiro PII: DOI: Reference:
S1935-861X(16)30003-1 http://dx.doi.org/doi: 10.1016/j.brs.2016.02.001 BRS 850
To appear in:
Brain Stimulation
Received date:
2-1-2016
Please cite this article as: Alisson Paulino Trevizol, Pedro Shiozawa, Ivan Taiar, Amanda Soares, July Silveira Gomes, Mirna Duarte Barros, Bianca Maria Liquidato, Quirino Cordeiro, Transcutaneous Vagus Nerve Stimulation (taVNS) for Major Depressive Disorder: an Open Label Proof-of-Concept Trial, Brain Stimulation (2016), http://dx.doi.org/doi: 10.1016/j.brs.2016.02.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Transcutaneous Vagus Nerve Stimulation (taVNS) for Major Depressive Disorder: An open label proof-of-concept trial Alisson Paulino Trevizol(1); Pedro Shiozawa(1); Ivan Taiar(1); Amanda Soares(1); July Silveira Gomes(1); Mirna Duarte Barros(1); Bianca Maria Liquidato(1); Quirino Cordeiro(1)
Interdisciplinary Center for Clinical Neuromodulation, Santa Casa School of Med, Brazil The present work was performed at t , Brazil Running title: TaVNS for MDD - An open-label proof-of-concept trial Declaration of interest: All authors confirm that this manuscript has not been published elsewhere and is not under consideration by another Journal. All authors have approved the manuscript and agree with its submission to Brain Stimulation. We here declare no conflict of interest related to the present manuscript.
Key words: Major Depressive Disorder; Depression; Depressive Disorder; TreatmentResistant Depressive Disorder; Brain Stimulation; Vagus Nerve Stimulation
Correspondence: Alisson Paulino Trevizol; Departamento de Psiquiatria, Faculdade de Ciências Médicas da Santa Casa de São Paulo; Rua Major Maragliano, 241 Vila Mariana;
04600-010
São
Paulo
SP,
Brasil;
+55113466-2200.
E-mail:
[email protected].
Page 1 of 7
Dear Editor, Despite recent advances in pharmacological treatments, Major Depressive Disorder (MDD) remains an incapacitating psychiatric condition with increasing prevalence and economic burden[1]. New therapeutical strategies such as vagus nerve stimulation (VNS) are being studied [2]. Different brain sites can be modulated by using electrical currents, which can theoretically restore balance to impaired circuits leading to clinical amelioration of symptoms. VNS involves the direct stimulation of the vagus nerve leading to further modulation of impaired brain areas related to psychiatric disorders[3; 4]. Target stimulated areas include solitary tract nucleus, dorsal raphe, locus coeruleus, parabrachial area, amygdala, nucleus accumbent, hippocampus and the dorsolateral prefrontal cortex (DLPFC) [5]. Non-invasive VNS stimulation protocols have been assessed with promising results [6]. In fact, our group and others have recently proposed a hypothetically safer non-invasive approach for transcutaneously stimulating the vagus nerve in the ear, transcutaneous auricular VNS (taVNS) [7]. There are also methods for non-invasively stimulating the vagus nerve in the neck, or cervical region, called transcutaneous cervical VNS (tcVNS). We undertook this proof-of-concept study to evaluate both the safety and potential clinical efficacy of this new experimental protocol with taVNS for treating patients with MDD. The present protocol had institutional review board. Patients diagnosed with MDD according to the DSM-V criteria were recruited in an outpatient university hospital clinic. Symptom severity was assessed by the 17-item Hamilton Depression Rating Scale (HDRS). Exploratory analyses assessed depressive symptoms through the Beck
Page 2 of 7
Depression Inventory (BDI), anxiety symptoms through the Hamilton Anxiety Rating Scale (HAMA) and the Beck Anxiety Inventory (BAI), sleep quality through the Pittsburgh Sleep Quality Index (PSQI), and somatic symptoms through the Somatic Symptom Inventory (SSI) and the Somatoform Disorders Screening Instrument-7 days (SOMS-7). We also assessed cognitive functions with the Montreal Cognitive Assessment instrument (MoCA). Inclusion criteria were as follows: (1) 18- to 59-year-old patients, (2) patients diagnosed with MDD following DSM-V criteria, (3) agreement to participate in the trial with written informed consent. Exclusion criteria were the following: (1) imminent need for psychiatric hospitalization, (2) any other [current or lifetime] psychiatric diagnosis, (3) neurologic or other severe diseases such as neoplastic syndromes and neurodegenerative and uncompensated chronic comorbidities, and (4) pregnancy. Clinical assessment was performed by a trained psychiatrist at baseline, at the last day of the stimulation protocol and one month after. The primary outcome was assessed by the mean difference in HDRS scores between baseline and the last day of stimulation. Participants were required to have at least four weeks without a change in psychiatric medication before the beginning of taVNS stimulation until the end of the one-month follow-up period. All patients underwent a 10-session taVNS protocol during a two-week period. Electrical Stimulation was performed using the Ibramed Neurodyn II external neurostimulator to deliver electric current through the auricular branch of the vagus nerve at 120 Hz with a pulse wave duration of 250µs for 30 minutes per day. The intensity was set at 12mA, which provoked a nonpainful mild paresthesia without muscle
Page 3 of 7
contraction for all patients. We performed the stimulation placing the electrodes bilaterally over the mastoid process area (anode to the left and cathode to the right), juxtaposed to the ear, near the tympanomastoid fissure (see Figure)[8]. We used 15cm2 auto-adhesive rubber electrodes to deliver the current. The main outcome and exploratory analyses were tested using ANOVA and paired t-tests. Intention-to-treat analysis was performed using the last observation carw
gw
g
.T
α
level was set at 0.05. Statistical analysis was performed using the standard statistical software Stata 13.1. Sample size calculation was based on the algorithm proposed by A'Hern for single-stage trials[9]. A total of twelve patients were recruited, with a mean age of 45.9 years (sd=9, range 32 to 57). Two patients were male. Mean time since first episode was of 7.5 years (sd=7.7). There was no dropout. The mean baseline HDRS was 27.9 (sd=4.2). All patients were under stable pharmacological protocol for at least four weeks. Treatment remained unchanged during the one-month follow-up period. Regarding the main outcome, at the end of intervention there was a reduction of MDD symptoms from 27.9 (sd=4.2) to 8.2 (sd=4) (mean difference of 19.75 (sd=4.5)) (p<0.001) on the HDRS instrument. Considering a categorical analysis, all patients exhibited a clinical response, defined as a reduction of HDRS scores of at least 50%. Five patients presented remission of depressive symptoms defined as less than 8 points on the HDRS. Clinical response was maintained stable during the one month-follow-up period. Cognitive functioning remained stable as assessed by the MoCA (p= 0.57) (see table).
Page 4 of 7
All patients reported mild paresthesia underneath the electrodes during stimulation. No severe adverse effects were reported. Ten patients reported mild to moderate diurnal sleepiness after the stimulation protocol, which they attributed to the procedure. Six patients reported mild to moderate tension headaches, with no need for medication. Four patients reported mild to moderate nausea. No side effects were reported at onemonth follow-up. In the current experimental protocol, we theoretically transcutaneously accessed the auricular branch of the vagus nerve. This particular branch penetrates the mastoid canaliculus, accessing the temporal bone and emerges through the tympanomastoid fissure[7]. It then originates two branches, one that enervates the occipitofrontal muscle with the posterior auricular nerve and another branch that enervates the skin over the mastoid process and the posterior wall of the ear canal[8]. The studied 10-day taVNS protocol led to amelioration of MDD symptoms, with no severe adverse effects. Based on an easy-to-use and non-invasive technology, the present approach, if replicated in larger, more rigorous trials, may be helpful for patients with psychiatric disorders in which the neurobiology involves the vagus nerve subcortical and cortical connections, such as the amygdala, the hippocampus and the DLPFC. Our results, however, need to be analyzed under more rigorous studies that are larger and fully double blind.
Bibliography
Page 5 of 7
1.
Nock MK, Kessler RC. Prevalence of and risk factors for suicide attempts versus
suicide gestures: analysis of the National Comorbidity Survey. J Abnorm Psychol 2006;115(3):616-23. 2.
George MS. Brain stimulation, as a field, continues to evolve and expand. From
the Editor-in-Chief's desk. Brain Stimul 2010;3(2):63-4. 3.
George MS, Ward HE, Jr., Ninan PT et al. . A pilot study of vagus nerve stimula-
tion (VNS) for treatment-resistant anxiety disorders. Brain Stimul 2008;1(2):112-21. 4.
George MS, Aston-Jones G. Noninvasive techniques for probing neurocircuitry
and treating illness: vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). Neuropsychopharmacology 2010;35(1):301-16. 5.
Frangos E, Ellrich J, Komisaruk BR. Non-invasive Access to the Vagus Nerve
Central Projections via Electrical Stimulation of the External Ear: fMRI Evidence in Humans. Brain Stimul 2015;8(3):624-36. 6.
Hein E, Nowak M, Kiess O et al. . Auricular transcutaneous electrical nerve sti-
mulation in depressed patients: a randomized controlled pilot study. J Neural Transm 2013;120(5):821-7. 7.
Trevizol A, Barros MD, Liquidato B et al. . Vagus nerve stimulation in neuropsy-
chiatry: Targeting anatomy-based stimulation sites. Epilepsy Behav 2015;51:18. 8.
Trevizol AP, Taiar I, Barros MD et al. . Transcutaneous vagus nerve stimulation
(tVNS) protocol for the treatment of major depressive disorder: A case study assessing the auricular branch of the vagus nerve. Epilepsy Behav 2015;53:166-7.
Page 6 of 7
9.
A'Hern RP. Sample size tables for exact single-stage phase II designs. Stat Med
2001;20(6):859-66.
Figure: Anode positioning over the mastoid process area, juxtaposed to the ear. The cathode was positioned in the same way over the right mastoid process area. Table: Summary of clinical outcomes. Baseline (sd) Day 10 (sd) Day 45 (sd)
F
df
p
HDRS
27.9 (4.2)
8.17 (4)
8.75 (4.8)
81.1
2
<0.001
HAMA
33.3 (5.2)
6.5 (5.3)
7.2 (6.3)
87.9
2
<0.001
BDI
37.3 (9.9)
19.7 (12.7)
16.4 (14.2)
9.87
2
<0.001
BAI
41.5 (14.2)
20.8 (14.4)
18.2 (16.2)
8.72
2
<0.001
PSQI
13.7 (3.1)
5.7 (2.3)
6.4 (4)
22.07
2
<0.001
SOMS-7
19.75 (9.7)
5.7 (6.5)
4.8 (6.8)
14.32
2
<0.001
SSI
35.7 (6.9)
27.9 (3.3)
28.2 (3.2)
10.12
2
<0.001
MoCA
21.75 (4.6)
22.4 (4)
23.6 (4.2)
0.57
2
0.57
HDRS= Hamilton Depression Rating Scale with 17 items, HAMA= Hamilton Anxiety Rating Scale, BDI= Beck Depression Inventory, BAI= Beck Anxiety Inventory, PSQI= Pittsburgh Sleep Quality Index, SOMS-7= Somatoform Disorders Screening Instrument-7 days, SSI- Somatic Symptom Inventory, MoCA= Montreal Cognitive Assessment, sd= standard deviation, df= degrees of freedom.
Page 7 of 7
S1935-861X(16)30003-1 http://dx.doi.org/doi: 10.1016/j.brs.2016.02.001 BRS 850
To appear in:
Brain Stimulation
Received date:
2-1-2016
Please cite this article as: Alisson Paulino Trevizol, Pedro Shiozawa, Ivan Taiar, Amanda Soares, July Silveira Gomes, Mirna Duarte Barros, Bianca Maria Liquidato, Quirino Cordeiro, Transcutaneous Vagus Nerve Stimulation (taVNS) for Major Depressive Disorder: an Open Label Proof-of-Concept Trial, Brain Stimulation (2016), http://dx.doi.org/doi: 10.1016/j.brs.2016.02.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Transcutaneous Vagus Nerve Stimulation (taVNS) for Major Depressive Disorder: An open label proof-of-concept trial Alisson Paulino Trevizol(1); Pedro Shiozawa(1); Ivan Taiar(1); Amanda Soares(1); July Silveira Gomes(1); Mirna Duarte Barros(1); Bianca Maria Liquidato(1); Quirino Cordeiro(1)
Interdisciplinary Center for Clinical Neuromodulation, Santa Casa School of Med, Brazil The present work was performed at t , Brazil Running title: TaVNS for MDD - An open-label proof-of-concept trial Declaration of interest: All authors confirm that this manuscript has not been published elsewhere and is not under consideration by another Journal. All authors have approved the manuscript and agree with its submission to Brain Stimulation. We here declare no conflict of interest related to the present manuscript.
Key words: Major Depressive Disorder; Depression; Depressive Disorder; TreatmentResistant Depressive Disorder; Brain Stimulation; Vagus Nerve Stimulation
Correspondence: Alisson Paulino Trevizol; Departamento de Psiquiatria, Faculdade de Ciências Médicas da Santa Casa de São Paulo; Rua Major Maragliano, 241 Vila Mariana;
04600-010
São
Paulo
SP,
Brasil;
+55113466-2200.
E-mail:
[email protected].
Page 1 of 7
Dear Editor, Despite recent advances in pharmacological treatments, Major Depressive Disorder (MDD) remains an incapacitating psychiatric condition with increasing prevalence and economic burden[1]. New therapeutical strategies such as vagus nerve stimulation (VNS) are being studied [2]. Different brain sites can be modulated by using electrical currents, which can theoretically restore balance to impaired circuits leading to clinical amelioration of symptoms. VNS involves the direct stimulation of the vagus nerve leading to further modulation of impaired brain areas related to psychiatric disorders[3; 4]. Target stimulated areas include solitary tract nucleus, dorsal raphe, locus coeruleus, parabrachial area, amygdala, nucleus accumbent, hippocampus and the dorsolateral prefrontal cortex (DLPFC) [5]. Non-invasive VNS stimulation protocols have been assessed with promising results [6]. In fact, our group and others have recently proposed a hypothetically safer non-invasive approach for transcutaneously stimulating the vagus nerve in the ear, transcutaneous auricular VNS (taVNS) [7]. There are also methods for non-invasively stimulating the vagus nerve in the neck, or cervical region, called transcutaneous cervical VNS (tcVNS). We undertook this proof-of-concept study to evaluate both the safety and potential clinical efficacy of this new experimental protocol with taVNS for treating patients with MDD. The present protocol had institutional review board. Patients diagnosed with MDD according to the DSM-V criteria were recruited in an outpatient university hospital clinic. Symptom severity was assessed by the 17-item Hamilton Depression Rating Scale (HDRS). Exploratory analyses assessed depressive symptoms through the Beck
Page 2 of 7
Depression Inventory (BDI), anxiety symptoms through the Hamilton Anxiety Rating Scale (HAMA) and the Beck Anxiety Inventory (BAI), sleep quality through the Pittsburgh Sleep Quality Index (PSQI), and somatic symptoms through the Somatic Symptom Inventory (SSI) and the Somatoform Disorders Screening Instrument-7 days (SOMS-7). We also assessed cognitive functions with the Montreal Cognitive Assessment instrument (MoCA). Inclusion criteria were as follows: (1) 18- to 59-year-old patients, (2) patients diagnosed with MDD following DSM-V criteria, (3) agreement to participate in the trial with written informed consent. Exclusion criteria were the following: (1) imminent need for psychiatric hospitalization, (2) any other [current or lifetime] psychiatric diagnosis, (3) neurologic or other severe diseases such as neoplastic syndromes and neurodegenerative and uncompensated chronic comorbidities, and (4) pregnancy. Clinical assessment was performed by a trained psychiatrist at baseline, at the last day of the stimulation protocol and one month after. The primary outcome was assessed by the mean difference in HDRS scores between baseline and the last day of stimulation. Participants were required to have at least four weeks without a change in psychiatric medication before the beginning of taVNS stimulation until the end of the one-month follow-up period. All patients underwent a 10-session taVNS protocol during a two-week period. Electrical Stimulation was performed using the Ibramed Neurodyn II external neurostimulator to deliver electric current through the auricular branch of the vagus nerve at 120 Hz with a pulse wave duration of 250µs for 30 minutes per day. The intensity was set at 12mA, which provoked a nonpainful mild paresthesia without muscle
Page 3 of 7
contraction for all patients. We performed the stimulation placing the electrodes bilaterally over the mastoid process area (anode to the left and cathode to the right), juxtaposed to the ear, near the tympanomastoid fissure (see Figure)[8]. We used 15cm2 auto-adhesive rubber electrodes to deliver the current. The main outcome and exploratory analyses were tested using ANOVA and paired t-tests. Intention-to-treat analysis was performed using the last observation carw
gw
g
.T
α
level was set at 0.05. Statistical analysis was performed using the standard statistical software Stata 13.1. Sample size calculation was based on the algorithm proposed by A'Hern for single-stage trials[9]. A total of twelve patients were recruited, with a mean age of 45.9 years (sd=9, range 32 to 57). Two patients were male. Mean time since first episode was of 7.5 years (sd=7.7). There was no dropout. The mean baseline HDRS was 27.9 (sd=4.2). All patients were under stable pharmacological protocol for at least four weeks. Treatment remained unchanged during the one-month follow-up period. Regarding the main outcome, at the end of intervention there was a reduction of MDD symptoms from 27.9 (sd=4.2) to 8.2 (sd=4) (mean difference of 19.75 (sd=4.5)) (p<0.001) on the HDRS instrument. Considering a categorical analysis, all patients exhibited a clinical response, defined as a reduction of HDRS scores of at least 50%. Five patients presented remission of depressive symptoms defined as less than 8 points on the HDRS. Clinical response was maintained stable during the one month-follow-up period. Cognitive functioning remained stable as assessed by the MoCA (p= 0.57) (see table).
Page 4 of 7
All patients reported mild paresthesia underneath the electrodes during stimulation. No severe adverse effects were reported. Ten patients reported mild to moderate diurnal sleepiness after the stimulation protocol, which they attributed to the procedure. Six patients reported mild to moderate tension headaches, with no need for medication. Four patients reported mild to moderate nausea. No side effects were reported at onemonth follow-up. In the current experimental protocol, we theoretically transcutaneously accessed the auricular branch of the vagus nerve. This particular branch penetrates the mastoid canaliculus, accessing the temporal bone and emerges through the tympanomastoid fissure[7]. It then originates two branches, one that enervates the occipitofrontal muscle with the posterior auricular nerve and another branch that enervates the skin over the mastoid process and the posterior wall of the ear canal[8]. The studied 10-day taVNS protocol led to amelioration of MDD symptoms, with no severe adverse effects. Based on an easy-to-use and non-invasive technology, the present approach, if replicated in larger, more rigorous trials, may be helpful for patients with psychiatric disorders in which the neurobiology involves the vagus nerve subcortical and cortical connections, such as the amygdala, the hippocampus and the DLPFC. Our results, however, need to be analyzed under more rigorous studies that are larger and fully double blind.
Bibliography
Page 5 of 7
1.
Nock MK, Kessler RC. Prevalence of and risk factors for suicide attempts versus
suicide gestures: analysis of the National Comorbidity Survey. J Abnorm Psychol 2006;115(3):616-23. 2.
George MS. Brain stimulation, as a field, continues to evolve and expand. From
the Editor-in-Chief's desk. Brain Stimul 2010;3(2):63-4. 3.
George MS, Ward HE, Jr., Ninan PT et al. . A pilot study of vagus nerve stimula-
tion (VNS) for treatment-resistant anxiety disorders. Brain Stimul 2008;1(2):112-21. 4.
George MS, Aston-Jones G. Noninvasive techniques for probing neurocircuitry
and treating illness: vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). Neuropsychopharmacology 2010;35(1):301-16. 5.
Frangos E, Ellrich J, Komisaruk BR. Non-invasive Access to the Vagus Nerve
Central Projections via Electrical Stimulation of the External Ear: fMRI Evidence in Humans. Brain Stimul 2015;8(3):624-36. 6.
Hein E, Nowak M, Kiess O et al. . Auricular transcutaneous electrical nerve sti-
mulation in depressed patients: a randomized controlled pilot study. J Neural Transm 2013;120(5):821-7. 7.
Trevizol A, Barros MD, Liquidato B et al. . Vagus nerve stimulation in neuropsy-
chiatry: Targeting anatomy-based stimulation sites. Epilepsy Behav 2015;51:18. 8.
Trevizol AP, Taiar I, Barros MD et al. . Transcutaneous vagus nerve stimulation
(tVNS) protocol for the treatment of major depressive disorder: A case study assessing the auricular branch of the vagus nerve. Epilepsy Behav 2015;53:166-7.
Page 6 of 7
9.
A'Hern RP. Sample size tables for exact single-stage phase II designs. Stat Med
2001;20(6):859-66.
Figure: Anode positioning over the mastoid process area, juxtaposed to the ear. The cathode was positioned in the same way over the right mastoid process area. Table: Summary of clinical outcomes. Baseline (sd) Day 10 (sd) Day 45 (sd)
F
df
p
HDRS
27.9 (4.2)
8.17 (4)
8.75 (4.8)
81.1
2
<0.001
HAMA
33.3 (5.2)
6.5 (5.3)
7.2 (6.3)
87.9
2
<0.001
BDI
37.3 (9.9)
19.7 (12.7)
16.4 (14.2)
9.87
2
<0.001
BAI
41.5 (14.2)
20.8 (14.4)
18.2 (16.2)
8.72
2
<0.001
PSQI
13.7 (3.1)
5.7 (2.3)
6.4 (4)
22.07
2
<0.001
SOMS-7
19.75 (9.7)
5.7 (6.5)
4.8 (6.8)
14.32
2
<0.001
SSI
35.7 (6.9)
27.9 (3.3)
28.2 (3.2)
10.12
2
<0.001
MoCA
21.75 (4.6)
22.4 (4)
23.6 (4.2)
0.57
2
0.57
HDRS= Hamilton Depression Rating Scale with 17 items, HAMA= Hamilton Anxiety Rating Scale, BDI= Beck Depression Inventory, BAI= Beck Anxiety Inventory, PSQI= Pittsburgh Sleep Quality Index, SOMS-7= Somatoform Disorders Screening Instrument-7 days, SSI- Somatic Symptom Inventory, MoCA= Montreal Cognitive Assessment, sd= standard deviation, df= degrees of freedom.
Page 7 of 7