- Email: [email protected]
Rapid titration protocol – Experiences with a dynamic novel titration regime for vagus nerve stimulation in a group of depressive patients
Journal of Clinical Neuroscience xxx (xxxx) xxx
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Short communication
Rapid titration protocol – Experiences with a dynamic novel titration regime for vagus nerve stimulation in a group of depressive patients Sebastian Moeller a,⇑, Ruihao Wang b, Merve Aydin a, Alexandra P. Lam a, Aileen Sitter a, Jonas Grüter a, Alexandra Philipsen a, Helge H.O. Müller a a b
Universitätsklinikum Bonn AöR, Klinik und Poliklinik für Psychiatrie, Bonn, Germany Universitätsklinikum Erlangen, Klinik und Poliklinik für Neurologie, Erlangen, Germany
a r t i c l e
i n f o
Article history: Received 27 June 2019 Accepted 8 August 2019 Available online xxxx Keywords: Vagus nerve Therapy-resistant depression Vagus nerve stimulation VNS TRD Dosing
a b s t r a c t Vagus nerve stimulation (VNS) is an established tool in the psychiatric armamentarium for patients with therapy-resistant depression (TRD) with response rates of approximately 60%. So far, VNS is titrated slowly during ambulatory in-office visits. Thus, antidepressive effects can be expected after approximately six months. We report our experiences with a rapid dosing regime (RDR) with titration start shortly after VNSimplantation. We retrospectively analysed data of six patients with TRD who received VNS. Stimulation parameters were evaluated with regard to clinical side effects, heart rates (HR) and blood pressures (BP). Depressive symptoms were measured by Montgomery-Asberg Depression Rating Scale (MADRS) one week before and three months after implantation of the VNS. All patients received first stimulation between one and four days after surgery. We elevated output current using 0.25 mA titration steps. We increased output current between one and four days after the last titration. All patients received 1.0 mA output current after eight to 14 days post-surgery. HR and BP remained stable in all patients. All side effects were mild and temporary. MADRS scores were significantly lower three months after VNS-implantation (24 ± 8) than one week before VNS-implantation (42 ± 4; p = 0.028). The therapeutic range of VNS-parameters for antidepressive effect was reached quicker without finding increased numbers of side effects. Consequently, by using RDR the antidepressive effect of VNS-therapy for patients with TRD could be reached earlier than using slow titration. Our presented RDR might be able to significantly shorten the ‘‘clinical effect gap” due to the neurobiological and titration-related latency. Ó 2019 Elsevier Ltd. All rights reserved.
1. Introduction Vagus nerve stimulation is an established tool in the psychiatric armamentarium for patients with therapy-resistant depression (TRD) [1–4]. TRD is defined as the failure of two successive trials of antidepressant treatment administered at an appropriate dose and for sufficient duration [5,6]. Using VNS, approximately 60% of patients with TRD show reduction in their depressive symptoms [1,2]. Long-term follow-ups indicate fewer suicide attempts, lower levels of suicidal ideations and thoughts, and fewer hospitaliza⇑ Corresponding author at: Department of Psychiatry and Psychotherapy, Universitätsklinikum Bonn, Venusberg-Campus 1, 53127 Bonn, Germany. E-mail addresses: [email protected] (S. Moeller), ruihao.wang@ uk-erlangen.de (R. Wang), [email protected] (M. Aydin), alexandra.lam@ ukbonn.de (A.P. Lam), [email protected] (A. Sitter), [email protected] (J. Grüter), [email protected] (A. Philipsen), helge.mueller@ukbonn. de (H.H.O. Müller).
tions in patients treated with VNS in addition to pharmacotherapy compared to patients with the same level of depression symptom severity who were only treated with pharmacotherapy [2,4,7]. According to clinical expertise, VNS stimulation begins two weeks after implantation [8]. The treating physician uses a handheld computer and telemetric wand to modulate the stimulation parameters. Frequent ambulatory in-office visits are needed to set-up the parameters of the stimulator [4]. Here, we report our positive findings of a rapid dose titration regime starting immediately after implantation of VNS. 2. Material and methods In this study, data of six patients who received VNS were analyzed retrospectively (Table 1). Stimulation parameters, i.e. Output Current (mA), Signal Frequency (Hz), Pulse Width (msec), Signal On-Time (s), and Signal Off-Time (min), as well as concomitant
https://doi.org/10.1016/j.jocn.2019.08.071 0967-5868/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: S. Moeller, R. Wang, M. Aydin et al., Rapid titration protocol – Experiences with a dynamic novel titration regime for vagus nerve stimulation in a group of depressive patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.071
2
S. Moeller et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
Table 1 Output Current (mA), Signal Frequency (Hz), Pulse Width (msec), Signal On-Time (sec), Signal Off-Time (min) and Magnet Output Current (mA), concomitant pharmacotherapy, clinical side effects, blood pressures (mmHg) and heart rates (bpm) in six patients before stimulation and during the rapid titration period Pat- patient, OC – output current, mA – Milliamps, SF – Signal Frequency, HZ – Hertz, PW- Pulse Width, ms – Microseconds, On – On-time, s – seconds, Off – Off-time, min – minutes, HR – heart rate, bpm – peats per minute, BP – blood pressure, mm/Hg – millimetre of mercury. Pat
gender
age
Diagnosis
Days after surgery
OC (mA)
SF (Hz)
PW (ms)
On (s)
Off (min)
HR (bpm)
BP (mm/ Hg)
Side effects
Psychopharmacotherapy
1
f
60
TRD
1
0
0
0
0
0
70
130/80
Anxiety Disorder
1 7 10 14
0.25 0.5 0.75 1.0
30 30 30 30
500 500 500 500
30 30 30 30
10 10 10 10
68 72 69 67
120/80 130/75 125/80 130/80
Before stimulation Hoarseness Coughing Coughing Coughing
Venlafaxine ret. 225 mg-0–0 Mirtazapine 0–0-45 mg Olanzapine 0–0–0–5 mg Promethazine on request
TRD
1
0
0
0
0
0
82
130/90
Escitalopram 15 mg-0–0–0 Mirtazapine 0–0-7.5 mg
1 3 6 9 12
0.25 0.5 0.75 1.0 1.25
30 30 30 30 30
500 500 500 500 500
30 30 30 30 30
5 5 5 5 5
88 84 70 80 88
130/90 125/85 125/90 130/80 120/80
Before stimulation Hoarseness Hoarseness Mild pain Hoarseness Hoarseness
1
0
0
0
0
0
73
120/80
1 3 6 8
0.25 0.5 0.75 1.0
30 30 30 30
500 500 500 500
30 30 30 30
5 5 5 5
75 72 74 71
120/80 125/80 120/85 120/80
Before stimulation Hoarseness – – –
Valproate 600 mg-0–600 mg Lamotrigine 50 mg-0–50 mg Prothipendyl 0–0–0–80 mg
TRD
1
0
0
0
0
0
76
120/80
Anxiety Disorder
2 5 6 12
0.25 0.5 0.75 1.0
30 30 30 30
500 500 500 500
30 30 30 30
5 10 10 10
72 74 84 68
110/80 120/80 110/70 110/80
Before stimulation – Hoarseness Hoarseness Hoarseness
Bupropion 300 mg-0–0 Mirtazapine 0–0–0–45 mg Pipamperone 0–20 mg20 mg–20 mg Pregabalin 75–0-75 mg
TRD
1
0
0
0
0
0
84
130/80
Milnacipran 50 mg-50 mg-0 Mirtazapine 0–0–0–7.5 mg
3 5 7 10
0.25 0.5 0.75 1.0
30 30 30 30
500 500 500 500
30 30 30 30
5 5 5 5
84 88 80 88
140/90 130/80 140/90 125/80
Before stimulation Hoarseness Hoarseness Hoarseness Hoarseness
1
0
0
0
0
0
88
125/80
4 5 6 8
0.25 0.5 0.75 1.0
30 30 30 30
500 500 500 500
30 30 30 30
5 5 5 5
84 82 92 90
130/84 130/80 130/90 125/90
Before stimulation Hoarseness – – Hoarseness
Quetiapine 0–0–0–50 mg Quetiapine ret. 0–0–0– 200 mg
2
3
4
5
6
m
m
m
m
f
37
44
55
38
56
TRD
TRD
pharmacotherapy, were evaluated consequently with regard to common clinical side effects of VNS, blood pressures (mmHg) and heart rates (bpm). Depressive symptoms were assessed via Montgomery-Asberg Depression Rating Scale (MADRS) [9]. The MADRS was administered one week before implantation of the vagus nerve stimulator and three months after implantation. We tested for normal distribution using the Shapiro-Wilk test. Correlation between different time points (before stimulation and during the titration period) and heart rates as well as systolic and diastolic blood pressures was assessed via Spearman rank correlation testing. Differences in MADRS scores were assessed by Wilcoxon-test for paired samples.
3. Results The first titration period was done in an in-patient setting. All patients received first stimulation between one and four days after surgery, which is a novel titration regime first presented herein. First dosing parameters in all patients were as follows: Output Current 0.25 mA, Signal Frequency 30 Hz, Pulse Width 500 msec, Signal On-Time 30 s and Signal Off-Time 5 min (except one female patient who had 10 min Off-Time). We elevated the output current using 0.25 mA titration steps. We increased the output current between one and four days after last titration. All patients received 1.0 mA
output current after eight to 14 days post-surgery. In all patients heart rates and blood pressures did not correlate with the different time points (p > 0.05). Hoarseness was observed in all patients, coughing and pain was reported by only one patient each. All side effects were mild and temporary. There were no side effects on the central nervous system. MADRS scores were significantly lower three months after surgery (mean ± SD: 24 ± 8) than one week before VNS implantation (42 ± 4; p = 0.028) (Fig. 1).
4. Discussion Our preliminary data support the conclusion that a rapid dosing regime for VNS is safe and does not lead to an increased number of harmful side effects. Usually, dosing titration starts two weeks after surgery [4] and stimulation is increased by 0.25 mA per visit during psychiatric in-office visits. Consequently, frequent visits are needed to reach the therapeutic range between 1.0 and 2.0 mA [3,4]. Thus, treatment results can be expected after approximately four to six months of VNS therapy [3,4]. Aaronson et al. showed that the total charge of the VNS delivered per day correlates with decreasing depressive symptoms [10]. Thus, to reach optimal effectiveness of VNS a preferably high output current would be desirable. Moreover, higher electrical dose parameters are associated with response durability [10]. Additionally, the stimulation
Please cite this article as: S. Moeller, R. Wang, M. Aydin et al., Rapid titration protocol – Experiences with a dynamic novel titration regime for vagus nerve stimulation in a group of depressive patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.071
S. Moeller et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
3
However, we are aware of the small sample size of only six patients. Thus, our preliminary results have to be controlled in larger clinical samples. Our presented dynamic dosing regime might be able to significantly shorten the ‘‘clinical effect gap” due to the neurobiological and titration-related latency [3,4]. Authors’ contributions S. Moeller and H.H.O. Müller wrote the manuscript. R. Wang, M. Aydin, A.P. Lam, A. Sitter, J. Grüter, A. Philipsen reviewed and revised the manuscript. Financial support
Fig. 1. Montgomery-Asberg Depression Rating Scale (MADRS) one week before implantation and three months after surgery.
amplitude must be optimized with respect to tolerability [3,4]. None of our patients had temporary side effects on the central nervous system, e.g. dizziness, fatigue, psychomotoric slowdown or cognitive impairment [11]. In the light of that findings the usual slow and careful increase of the output current of the VNS does not seem to be necessary. All our patients were programmed at minimally 1.0 mA output current within 14 days after implantation of the VNS, i.e. at the minimum therapeutic output current where antidepressive action can be expected. Although we only assessed six patients with severe major depressive disorder, depression severity in our sample measured by MADRS already significantly improved after three months. In our study the antidepressive effects were reached quicker than previously described [2]. Thus, severely depressed patients might reach remission earlier and have a sustained antidepressive effect with the newly described VNS dosing regime herein. This could be a valuable finding under the light of closing the gap in antidepressive treatment latency of VNS. Moreover, the side effects that occurred in our patient cohort were well known, only low in intensity and temporary. As the patients were on-ward physicians were able to immediately react to patient side effects. However, because of the only low and transient unwanted secondary effects it seems possible to perform a dynamic dosing regime also in an ambulatory setting. To conclude, for the first time we presented a dynamic novel titration regime for vagus nerve stimulation in severe depressive patients. Using the rapid dosing regime the full antidepressive VNS effect for patients could be reached earlier than using the slower titration regime during ambulatory in-office visits. We only observed the same local side effects which are known from the slow titration regime.
S. Moeller received a research grant from LivaNova, Inc. H.H.O. Müller served as an advisory board member of LivaNova, Inc. and received speaker’s compensation from LivaNova, Inc. M. Aydin, A. Philipsen, J. Grüter, H.H.O. Müller and S. Moeller received research funding from LivaNova as Universitätsklinikum Bonn participates in the ‘‘RESTORE-LIFE” study. A.P. Lam, A. Sitter and R. Wang report no disclosures. References [1] Müller HHO, Lücke C, Moeller S, Philipsen A, Sperling W. Efficacy and longterm tuning parameters of vagus nerve stimulation in long-term treated depressive patients. J Clin Neurosci 2017;44:340–1. https://doi.org/10.1016/j. jocn.2017.06.020. Epub Jul 1. [2] Aaronson ST, Sears P, Ruvuna F, Bunker M, Conway CR, Dougherty DD, et al. A 5-year observational study of patients with treatment-resistant depression treated with vagus nerve stimulation or treatment as usual: comparison of response, remission, and suicidality. Am J Psychiatry 2017;174:640–8. https:// doi.org/10.1176/appi.ajp.2017.16010034. Epub 2017 Mar 31. [3] Muller HHO, Moeller S, Lucke C, Lam AP, Braun N, Philipsen A. Vagus Nerve Stimulation (VNS) and other augmentation strategies for therapy-resistant depression (TRD): review of the evidence and clinical advice for use. Front Neurosci 2018;12(239). https://doi.org/10.3389/fnins.2018.00239. eCollection 2018. [4] Moeller S, Lucke C, Heinen C, Bewernick BH, Aydin M, Lam AP, et al. Vagus nerve stimulation as an adjunctive neurostimulation tool in treatmentresistant depression. J Vis Exp 2019. [5] Bschor T. Therapy-resistant depression. Expert Rev Neurother 2010;10:77–86. [6] Holtzmann J, Richieri R, Saba G, Allaili N, Bation R, Moliere F, et al. How to define treatment-resistant depression? Presse Med 2016;45:323–8. [7] Cusin C, Dougherty DD. Somatic therapies for treatment-resistant depression: ECT, TMS, VNS, DBS. Biol Mood Anxiety Disord 2012;2(14). https://doi.org/ 10.1186/2045-5380-2-14. [8] LivaNova USA I. VNS TherapyÒ System Depression Physician’s Manual. 2019 [9] Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979;134:382–9. [10] Aaronson ST, Carpenter LL, Conway CR, Reimherr FW, Lisanby SH, Schwartz TL, et al. Vagus nerve stimulation therapy randomized to different amounts of electrical charge for treatment-resistant depression: acute and chronic effects. Brain Stimul 2013;6:631–40. [11] Beekwilder JP, Beems T. Overview of the clinical applications of vagus nerve stimulation. J Clin Neurophysiol 2010;27:130–8.
Please cite this article as: S. Moeller, R. Wang, M. Aydin et al., Rapid titration protocol – Experiences with a dynamic novel titration regime for vagus nerve stimulation in a group of depressive patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.071
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Short communication
Rapid titration protocol – Experiences with a dynamic novel titration regime for vagus nerve stimulation in a group of depressive patients Sebastian Moeller a,⇑, Ruihao Wang b, Merve Aydin a, Alexandra P. Lam a, Aileen Sitter a, Jonas Grüter a, Alexandra Philipsen a, Helge H.O. Müller a a b
Universitätsklinikum Bonn AöR, Klinik und Poliklinik für Psychiatrie, Bonn, Germany Universitätsklinikum Erlangen, Klinik und Poliklinik für Neurologie, Erlangen, Germany
a r t i c l e
i n f o
Article history: Received 27 June 2019 Accepted 8 August 2019 Available online xxxx Keywords: Vagus nerve Therapy-resistant depression Vagus nerve stimulation VNS TRD Dosing
a b s t r a c t Vagus nerve stimulation (VNS) is an established tool in the psychiatric armamentarium for patients with therapy-resistant depression (TRD) with response rates of approximately 60%. So far, VNS is titrated slowly during ambulatory in-office visits. Thus, antidepressive effects can be expected after approximately six months. We report our experiences with a rapid dosing regime (RDR) with titration start shortly after VNSimplantation. We retrospectively analysed data of six patients with TRD who received VNS. Stimulation parameters were evaluated with regard to clinical side effects, heart rates (HR) and blood pressures (BP). Depressive symptoms were measured by Montgomery-Asberg Depression Rating Scale (MADRS) one week before and three months after implantation of the VNS. All patients received first stimulation between one and four days after surgery. We elevated output current using 0.25 mA titration steps. We increased output current between one and four days after the last titration. All patients received 1.0 mA output current after eight to 14 days post-surgery. HR and BP remained stable in all patients. All side effects were mild and temporary. MADRS scores were significantly lower three months after VNS-implantation (24 ± 8) than one week before VNS-implantation (42 ± 4; p = 0.028). The therapeutic range of VNS-parameters for antidepressive effect was reached quicker without finding increased numbers of side effects. Consequently, by using RDR the antidepressive effect of VNS-therapy for patients with TRD could be reached earlier than using slow titration. Our presented RDR might be able to significantly shorten the ‘‘clinical effect gap” due to the neurobiological and titration-related latency. Ó 2019 Elsevier Ltd. All rights reserved.
1. Introduction Vagus nerve stimulation is an established tool in the psychiatric armamentarium for patients with therapy-resistant depression (TRD) [1–4]. TRD is defined as the failure of two successive trials of antidepressant treatment administered at an appropriate dose and for sufficient duration [5,6]. Using VNS, approximately 60% of patients with TRD show reduction in their depressive symptoms [1,2]. Long-term follow-ups indicate fewer suicide attempts, lower levels of suicidal ideations and thoughts, and fewer hospitaliza⇑ Corresponding author at: Department of Psychiatry and Psychotherapy, Universitätsklinikum Bonn, Venusberg-Campus 1, 53127 Bonn, Germany. E-mail addresses: [email protected] (S. Moeller), ruihao.wang@ uk-erlangen.de (R. Wang), [email protected] (M. Aydin), alexandra.lam@ ukbonn.de (A.P. Lam), [email protected] (A. Sitter), [email protected] (J. Grüter), [email protected] (A. Philipsen), helge.mueller@ukbonn. de (H.H.O. Müller).
tions in patients treated with VNS in addition to pharmacotherapy compared to patients with the same level of depression symptom severity who were only treated with pharmacotherapy [2,4,7]. According to clinical expertise, VNS stimulation begins two weeks after implantation [8]. The treating physician uses a handheld computer and telemetric wand to modulate the stimulation parameters. Frequent ambulatory in-office visits are needed to set-up the parameters of the stimulator [4]. Here, we report our positive findings of a rapid dose titration regime starting immediately after implantation of VNS. 2. Material and methods In this study, data of six patients who received VNS were analyzed retrospectively (Table 1). Stimulation parameters, i.e. Output Current (mA), Signal Frequency (Hz), Pulse Width (msec), Signal On-Time (s), and Signal Off-Time (min), as well as concomitant
https://doi.org/10.1016/j.jocn.2019.08.071 0967-5868/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: S. Moeller, R. Wang, M. Aydin et al., Rapid titration protocol – Experiences with a dynamic novel titration regime for vagus nerve stimulation in a group of depressive patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.071
2
S. Moeller et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
Table 1 Output Current (mA), Signal Frequency (Hz), Pulse Width (msec), Signal On-Time (sec), Signal Off-Time (min) and Magnet Output Current (mA), concomitant pharmacotherapy, clinical side effects, blood pressures (mmHg) and heart rates (bpm) in six patients before stimulation and during the rapid titration period Pat- patient, OC – output current, mA – Milliamps, SF – Signal Frequency, HZ – Hertz, PW- Pulse Width, ms – Microseconds, On – On-time, s – seconds, Off – Off-time, min – minutes, HR – heart rate, bpm – peats per minute, BP – blood pressure, mm/Hg – millimetre of mercury. Pat
gender
age
Diagnosis
Days after surgery
OC (mA)
SF (Hz)
PW (ms)
On (s)
Off (min)
HR (bpm)
BP (mm/ Hg)
Side effects
Psychopharmacotherapy
1
f
60
TRD
1
0
0
0
0
0
70
130/80
Anxiety Disorder
1 7 10 14
0.25 0.5 0.75 1.0
30 30 30 30
500 500 500 500
30 30 30 30
10 10 10 10
68 72 69 67
120/80 130/75 125/80 130/80
Before stimulation Hoarseness Coughing Coughing Coughing
Venlafaxine ret. 225 mg-0–0 Mirtazapine 0–0-45 mg Olanzapine 0–0–0–5 mg Promethazine on request
TRD
1
0
0
0
0
0
82
130/90
Escitalopram 15 mg-0–0–0 Mirtazapine 0–0-7.5 mg
1 3 6 9 12
0.25 0.5 0.75 1.0 1.25
30 30 30 30 30
500 500 500 500 500
30 30 30 30 30
5 5 5 5 5
88 84 70 80 88
130/90 125/85 125/90 130/80 120/80
Before stimulation Hoarseness Hoarseness Mild pain Hoarseness Hoarseness
1
0
0
0
0
0
73
120/80
1 3 6 8
0.25 0.5 0.75 1.0
30 30 30 30
500 500 500 500
30 30 30 30
5 5 5 5
75 72 74 71
120/80 125/80 120/85 120/80
Before stimulation Hoarseness – – –
Valproate 600 mg-0–600 mg Lamotrigine 50 mg-0–50 mg Prothipendyl 0–0–0–80 mg
TRD
1
0
0
0
0
0
76
120/80
Anxiety Disorder
2 5 6 12
0.25 0.5 0.75 1.0
30 30 30 30
500 500 500 500
30 30 30 30
5 10 10 10
72 74 84 68
110/80 120/80 110/70 110/80
Before stimulation – Hoarseness Hoarseness Hoarseness
Bupropion 300 mg-0–0 Mirtazapine 0–0–0–45 mg Pipamperone 0–20 mg20 mg–20 mg Pregabalin 75–0-75 mg
TRD
1
0
0
0
0
0
84
130/80
Milnacipran 50 mg-50 mg-0 Mirtazapine 0–0–0–7.5 mg
3 5 7 10
0.25 0.5 0.75 1.0
30 30 30 30
500 500 500 500
30 30 30 30
5 5 5 5
84 88 80 88
140/90 130/80 140/90 125/80
Before stimulation Hoarseness Hoarseness Hoarseness Hoarseness
1
0
0
0
0
0
88
125/80
4 5 6 8
0.25 0.5 0.75 1.0
30 30 30 30
500 500 500 500
30 30 30 30
5 5 5 5
84 82 92 90
130/84 130/80 130/90 125/90
Before stimulation Hoarseness – – Hoarseness
Quetiapine 0–0–0–50 mg Quetiapine ret. 0–0–0– 200 mg
2
3
4
5
6
m
m
m
m
f
37
44
55
38
56
TRD
TRD
pharmacotherapy, were evaluated consequently with regard to common clinical side effects of VNS, blood pressures (mmHg) and heart rates (bpm). Depressive symptoms were assessed via Montgomery-Asberg Depression Rating Scale (MADRS) [9]. The MADRS was administered one week before implantation of the vagus nerve stimulator and three months after implantation. We tested for normal distribution using the Shapiro-Wilk test. Correlation between different time points (before stimulation and during the titration period) and heart rates as well as systolic and diastolic blood pressures was assessed via Spearman rank correlation testing. Differences in MADRS scores were assessed by Wilcoxon-test for paired samples.
3. Results The first titration period was done in an in-patient setting. All patients received first stimulation between one and four days after surgery, which is a novel titration regime first presented herein. First dosing parameters in all patients were as follows: Output Current 0.25 mA, Signal Frequency 30 Hz, Pulse Width 500 msec, Signal On-Time 30 s and Signal Off-Time 5 min (except one female patient who had 10 min Off-Time). We elevated the output current using 0.25 mA titration steps. We increased the output current between one and four days after last titration. All patients received 1.0 mA
output current after eight to 14 days post-surgery. In all patients heart rates and blood pressures did not correlate with the different time points (p > 0.05). Hoarseness was observed in all patients, coughing and pain was reported by only one patient each. All side effects were mild and temporary. There were no side effects on the central nervous system. MADRS scores were significantly lower three months after surgery (mean ± SD: 24 ± 8) than one week before VNS implantation (42 ± 4; p = 0.028) (Fig. 1).
4. Discussion Our preliminary data support the conclusion that a rapid dosing regime for VNS is safe and does not lead to an increased number of harmful side effects. Usually, dosing titration starts two weeks after surgery [4] and stimulation is increased by 0.25 mA per visit during psychiatric in-office visits. Consequently, frequent visits are needed to reach the therapeutic range between 1.0 and 2.0 mA [3,4]. Thus, treatment results can be expected after approximately four to six months of VNS therapy [3,4]. Aaronson et al. showed that the total charge of the VNS delivered per day correlates with decreasing depressive symptoms [10]. Thus, to reach optimal effectiveness of VNS a preferably high output current would be desirable. Moreover, higher electrical dose parameters are associated with response durability [10]. Additionally, the stimulation
Please cite this article as: S. Moeller, R. Wang, M. Aydin et al., Rapid titration protocol – Experiences with a dynamic novel titration regime for vagus nerve stimulation in a group of depressive patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.071
S. Moeller et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
3
However, we are aware of the small sample size of only six patients. Thus, our preliminary results have to be controlled in larger clinical samples. Our presented dynamic dosing regime might be able to significantly shorten the ‘‘clinical effect gap” due to the neurobiological and titration-related latency [3,4]. Authors’ contributions S. Moeller and H.H.O. Müller wrote the manuscript. R. Wang, M. Aydin, A.P. Lam, A. Sitter, J. Grüter, A. Philipsen reviewed and revised the manuscript. Financial support
Fig. 1. Montgomery-Asberg Depression Rating Scale (MADRS) one week before implantation and three months after surgery.
amplitude must be optimized with respect to tolerability [3,4]. None of our patients had temporary side effects on the central nervous system, e.g. dizziness, fatigue, psychomotoric slowdown or cognitive impairment [11]. In the light of that findings the usual slow and careful increase of the output current of the VNS does not seem to be necessary. All our patients were programmed at minimally 1.0 mA output current within 14 days after implantation of the VNS, i.e. at the minimum therapeutic output current where antidepressive action can be expected. Although we only assessed six patients with severe major depressive disorder, depression severity in our sample measured by MADRS already significantly improved after three months. In our study the antidepressive effects were reached quicker than previously described [2]. Thus, severely depressed patients might reach remission earlier and have a sustained antidepressive effect with the newly described VNS dosing regime herein. This could be a valuable finding under the light of closing the gap in antidepressive treatment latency of VNS. Moreover, the side effects that occurred in our patient cohort were well known, only low in intensity and temporary. As the patients were on-ward physicians were able to immediately react to patient side effects. However, because of the only low and transient unwanted secondary effects it seems possible to perform a dynamic dosing regime also in an ambulatory setting. To conclude, for the first time we presented a dynamic novel titration regime for vagus nerve stimulation in severe depressive patients. Using the rapid dosing regime the full antidepressive VNS effect for patients could be reached earlier than using the slower titration regime during ambulatory in-office visits. We only observed the same local side effects which are known from the slow titration regime.
S. Moeller received a research grant from LivaNova, Inc. H.H.O. Müller served as an advisory board member of LivaNova, Inc. and received speaker’s compensation from LivaNova, Inc. M. Aydin, A. Philipsen, J. Grüter, H.H.O. Müller and S. Moeller received research funding from LivaNova as Universitätsklinikum Bonn participates in the ‘‘RESTORE-LIFE” study. A.P. Lam, A. Sitter and R. Wang report no disclosures. References [1] Müller HHO, Lücke C, Moeller S, Philipsen A, Sperling W. Efficacy and longterm tuning parameters of vagus nerve stimulation in long-term treated depressive patients. J Clin Neurosci 2017;44:340–1. https://doi.org/10.1016/j. jocn.2017.06.020. Epub Jul 1. [2] Aaronson ST, Sears P, Ruvuna F, Bunker M, Conway CR, Dougherty DD, et al. A 5-year observational study of patients with treatment-resistant depression treated with vagus nerve stimulation or treatment as usual: comparison of response, remission, and suicidality. Am J Psychiatry 2017;174:640–8. https:// doi.org/10.1176/appi.ajp.2017.16010034. Epub 2017 Mar 31. [3] Muller HHO, Moeller S, Lucke C, Lam AP, Braun N, Philipsen A. Vagus Nerve Stimulation (VNS) and other augmentation strategies for therapy-resistant depression (TRD): review of the evidence and clinical advice for use. Front Neurosci 2018;12(239). https://doi.org/10.3389/fnins.2018.00239. eCollection 2018. [4] Moeller S, Lucke C, Heinen C, Bewernick BH, Aydin M, Lam AP, et al. Vagus nerve stimulation as an adjunctive neurostimulation tool in treatmentresistant depression. J Vis Exp 2019. [5] Bschor T. Therapy-resistant depression. Expert Rev Neurother 2010;10:77–86. [6] Holtzmann J, Richieri R, Saba G, Allaili N, Bation R, Moliere F, et al. How to define treatment-resistant depression? Presse Med 2016;45:323–8. [7] Cusin C, Dougherty DD. Somatic therapies for treatment-resistant depression: ECT, TMS, VNS, DBS. Biol Mood Anxiety Disord 2012;2(14). https://doi.org/ 10.1186/2045-5380-2-14. [8] LivaNova USA I. VNS TherapyÒ System Depression Physician’s Manual. 2019 [9] Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979;134:382–9. [10] Aaronson ST, Carpenter LL, Conway CR, Reimherr FW, Lisanby SH, Schwartz TL, et al. Vagus nerve stimulation therapy randomized to different amounts of electrical charge for treatment-resistant depression: acute and chronic effects. Brain Stimul 2013;6:631–40. [11] Beekwilder JP, Beems T. Overview of the clinical applications of vagus nerve stimulation. J Clin Neurophysiol 2010;27:130–8.
Please cite this article as: S. Moeller, R. Wang, M. Aydin et al., Rapid titration protocol – Experiences with a dynamic novel titration regime for vagus nerve stimulation in a group of depressive patients, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.071