Trial document




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  DRKS00016928

Trial Description

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Title

Heart rate variability and autonomic physiological functions as a predictor of clinical outcome in neurobiological stimulation therapy, in particular electroconvulsive therapy and vagus nerve stimulation

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Trial Acronym

HRV in neurobiological stimulation therapy

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URL of the Trial

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Brief Summary in Lay Language

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Brief Summary in Scientific Language

Although the efficacy and effectiveness of specific therapies for patients with depression are well established, it is still challenging to to predict the patient's response to the particular psychiatric therapy and the individual course of the disease. Patients with depression have an impairment of the autonomic nervous system (1-3). Berger et al. showed reduced cardiovascular modulation in depressed patients (4). Haj Kheder and colleagues found that in patients with severe Depression that gastric motility is reduced (5). Schumann and co-workers found in patients with severe depression differences in autonomically-mediated function of the baroreflex and various parameters of pupillary function compared to healthy volunteers (6). With clinical stabilization of the depressive symptoms, a normalization of the parameters of the cardiovascular-autonomic modulation could be observed in the patients (7).
In summary, patients with depression have elevated sympathetic ouflow, decreased parasympathetic activity, and a reduced sympathetic-mediated response to external stressors (6, 8-10). We assume that this even more severe in patients with severe depression (11, 12). 30-50% of all patients with severe depression do not achieve remission with available treatment options (13). This subtype of the disease is called therapy-resistant depression (TRD) (14-16). TRD is defined as a non-response of at least two treatments with antidepressant medication for a sufficiently long time and at a high enough dose (12, 17-19).
Neurobiological stimulation techniques, such as electroconvulsive therapy (ECT) or vagus nerve stimulation (VNS), are promising treatment options in patients with TRD (11). ECT is the oldest neurostimulation therapy used in patients with TRD (11). This is also the most common therapeutic option for severe and recurrent depression when medication and psychotherapy do not produce a sufficient therapeutic effect (11, 20-23). Based on data from six studies, a meta-analysis concluded that real ECT is significantly more effective than simulated (sham) ECT (24, 25). Changes in cardiovascular autonomic modulation before, during, and after ECT treatment could be a prognostic marker of response (26). Examination of patients with severe depression receiving ECT treatment showed that a high level of parasympathetic modulation at baseline was associated with a positive effect on ECT treatment (26). Furthermore, patients who responded well to ECT treatment showed an increase in parasympathetic activity (26, 27). However, the initial very good response of ECT is reduced by high relapse rates of up to 50% in patients with TRD (11, 28-31). As a result, e.g. so-called maintenance ECTs, in which the patient receives a significantly reduced number of new ECTs.
Alternatively, a vagus nerve stimulation can be performed with TRD (11). However, this does not expect an acute remission. The antidepressant effect only starts over a period of several months (11). The vagus nerve is stimulated with electrodes in the neck area. These electrodes are connected by a cable running under the skin to a stimulator that is implanted under the skin below the collarbone. The device can be programmed externally, e.g. to adjust the stimulus duration and stimulus intensity (11). Approximately 60% of patients with TRD show a reduction in their depressive symptoms (32-36). Follow-up of TRD patients receiving VNS treatment also indicates fewer attempts at suicide, lower suicidal thoughts and fewer hospitalizations (36-38). VNS induces effects on brain plasticity, causes changes in cerebral inflammatory responses and in particular leads to changes in the autonomic nervous system (39). The vagus nerve is responsible for the parasympathetic innervation of the large thoracic and abdominal organs, e.g. lungs and heart. Also essential are sensory afferent fibers from these organs, which reach various brain structures via the vagus nerve (40).
The stress hormone axis is considered an important mechanism for managing stressors. Cortisol and the high affinity glucocorticoid receptor (GR) play a key role in the regulation of the stress hormone axis. Hormonal activation triggers downstream cascades, which in turn are important for various cellular systems to process the respective stressors. Maintaining cellular homeostasis is a key target. Hormonal activation of GR is associated with homeostatic processes such as autophagy, which forms the basis for the breakdown of unwanted macromolecules, protein complexes, and organelles (41). Changes in the regulation of autophagy have been linked to depression as well as to the pharmacological treatment of depression (41, 42). There are evidences proving an effect of ECT on autophagic processes (41). In the following work we would like to further investigate this relationship.
We want to investigate whether the measurement of cardiovascular autonomic modulation and cortisol-induced autophagy in patients with TRD predicts the effectiveness of neurobiological stimulation procedures and whether a more accurate determination of the individual course of the disease is possible.

References
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2. Yeragani VK, Rao KA. Nonlinear measures of QT interval series: novel indices of cardiac repolarization lability: MEDqthr and LLEqthr. Psychiatry Res. 2003;117(2):177-90.
3. Yeragani VK, Roose S, Mallavarapu M, Radhakrishna RK, Pesce V. Major depression with ischemic heart disease: effects of paroxetine and nortriptyline on measures of nonlinearity and chaos of heart rate. Neuropsychobiology. 2002;46(3):125-35.
4. Berger S, Kliem A, Yeragani V, Bar KJ. Cardio-respiratory coupling in untreated patients with major depression. J Affect Disord. 2012;139(2):166-71.
5. Haj Kheder S, Heller J, Bar JK, Wutzler A, Menge BA, Juckel G. Autonomic dysfunction of gastric motility in major depression. J Affect Disord. 2018;226:196-202.
6. Schumann A, Andrack C, Bar KJ. Differences of sympathetic and parasympathetic modulation in major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2017;79(Pt B):324-31.
7. Voss A, Schulz S, Koschke M, Bar KJ. Linear and nonlinear analysis of autonomic regulation in depressed patients. Conf Proc IEEE Eng Med Biol Soc. 2008;2008:2653-6.
8. Sgoifo A, Carnevali L, Alfonso Mde L, Amore M. Autonomic dysfunction and heart rate variability in depression. Stress. 2015;18(3):343-52. doi: 10.3109/10253890.2015.1045868. Epub 2015 May 25.
9. Schulz S, Koschke M, Bar KJ, Voss A. The altered complexity of cardiovascular regulation in depressed patients. Physiol Meas. 2010;31(3):303-21.
10. Koschke M, Boettger MK, Schulz S, Berger S, Terhaar J, Voss A, et al. Autonomy of autonomic dysfunction in major depression. Psychosom Med. 2009;71(8):852-60.
11. 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.
12. Muller HHO, Lucke C, Moeller S, Philipsen A, Sperling W. Efficacy and long-term tuning parameters of vagus nerve stimulation in long-term treated depressive patients. J Clin Neurosci. 2017;44:340-1.
13. Schlaepfer TE, Agren H, Monteleone P, Gasto C, Pitchot W, Rouillon F, et al. The hidden third: improving outcome in treatment-resistant depression. J Psychopharmacol. 2012;26(5):587-602. doi: 10.1177/0269881111431748. Epub 2012 Jan 11.
14. Rush AJ, Kraemer HC, Sackeim HA, Fava M, Trivedi MH, Frank E, et al. Report by the ACNP Task Force on response and remission in major depressive disorder. Neuropsychopharmacology. 2006;31(9):1841-53.
15. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-17.
16. Mojtabai R. Nonremission and time to remission among remitters in major depressive disorder: revisiting STAR*D. Depress Anxiety. 2017.
17. Bschor T. Therapy-resistant depression. Expert Rev Neurother. 2010;10(1):77-86.
18. Holtzmann J, Richieri R, Saba G, Allaili N, Bation R, Moliere F, et al. [How to define treatment-resistant depression?]. Presse Med. 2016;45(3):323-8.
19. Wiles N, Thomas L, Abel A, Barnes M, Carroll F, Ridgway N, et al. Clinical effectiveness and cost-effectiveness of cognitive behavioural therapy as an adjunct to pharmacotherapy for treatment-resistant depression in primary care: the CoBalT randomised controlled trial. Health Technol Assess. 2014;18(31):1-167, vii-viii.
20. Kellner CH, Greenberg RM, Murrough JW, Bryson EO, Briggs MC, Pasculli RM. ECT in treatment-resistant depression. Am J Psychiatry. 2012;169(12):1238-44.
21. Kellner CH, Greenberg RM, Petrides G, Ahle GM, Adams DA, Liebman LS. Electroconvulsive Therapy Is a Noninvasive Brain Stimulation Technique. J ECT. 2016;32(1):70.
22. Kellner CH, Kaicher DC, Banerjee H, Knapp RG, Shapiro RJ, Briggs MC, et al. Depression severity in electroconvulsive therapy (ECT) versus pharmacotherapy trials. J ECT. 2015;31(1):31-3.
23. Kellner CH, Li EH. Electroconvulsive Therapy From Both Sides Now: Perspectives From Late and Early Career. J ECT. 2016;32(1):1-2.
24. Lima NN, Nascimento VB, Peixoto JA, Moreira MM, Neto ML, Almeida JC, et al. Electroconvulsive therapy use in adolescents: a systematic review. Ann Gen Psychiatry. 2013;12(1):17.
25. Group UER. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. Lancet. 2003;361(9360):799-808.
26. Ebert A, Jochum T, Ritter J, Boettger MK, Schulz S, Voss A, et al. Does parasympathetic modulation prior to ECT treatment influence therapeutic outcome? Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(7):1174-80.
27. Bar KJ, Ebert A, Boettger MK, Merz S, Kiehntopf M, Jochum T, et al. Is successful electroconvulsive therapy related to stimulation of the vagal system? J Affect Disord. 2010;125(1-3):323-9.
28. Kho KH, van Vreeswijk MF, Simpson S, Zwinderman AH. A meta-analysis of electroconvulsive therapy efficacy in depression. J ECT. 2003;19(3):139-47.
29. Rifkin A. ECT versus tricyclic antidepressants in depression: a review of the evidence. J Clin Psychiatry. 1988;49(1):3-7.
30. Pinna M, Manchia M, Oppo R, Scano F, Pillai G, Loche AP, et al. Clinical and biological predictors of response to electroconvulsive therapy (ECT): a review. Neurosci Lett. 2016.
31. Charlson F, Siskind D, Doi SA, McCallum E, Broome A, Lie DC. ECT efficacy and treatment course: a systematic review and meta-analysis of twice vs thrice weekly schedules. J Affect Disord. 2012;138(1-2):1-8.
32. Furmaga H, Shah A, Frazer A. Serotonergic and noradrenergic pathways are required for the anxiolytic-like and antidepressant-like behavioral effects of repeated vagal nerve stimulation in rats. Biol Psychiatry. 2011;70(10):937-45. doi: 10.1016/j.biopsych.2011.07.020. Epub Sep 9.
33. Muller HHO, Lucke C, Moeller S, Philipsen A, Sperling W. Efficacy and long-term tuning parameters of vagus nerve stimulation in long-term treated depressive patients. J Clin Neurosci. 2017;44:340-341.(doi):10.1016/j.jocn.2017.06.020. Epub Jul 1.
34. George MS, Rush AJ, Marangell LB, Sackeim HA, Brannan SK, Davis SM, et al. A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression. Biol Psychiatry. 2005;58(5):364-73. doi: 10.1016/j.biopsych.2005.07.028.
35. Shen H, Fuchino Y, Miyamoto D, Nomura H, Matsuki N. Vagus nerve stimulation enhances perforant path-CA3 synaptic transmission via the activation of beta-adrenergic receptors and the locus coeruleus. Int J Neuropsychopharmacol. 2012;15(4):523-30. doi: 10.1017/S1461145711000708. Epub 2011 May 17.
36. 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(7):640-8. doi: 10.1176/appi.ajp.2017.16010034. Epub 2017 Mar 31.
37. Burke MJ, Husain MM. Concomitant use of vagus nerve stimulation and electroconvulsive therapy for treatment-resistant depression. J ECT. 2006;22(3):218-22. doi: 10.1097/01.yct.0000230364.04240.52.
38. Rush AJ, Marangell LB, Sackeim HA, George MS, Brannan SK, Davis SM, et al. Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biol Psychiatry. 2005;58(5):347-54. doi: 10.1016/j.biopsych.2005.05.025.
39. Mertens A, Raedt R, Gadeyne S, Carrette E, Boon P, Vonck K. Recent advances in devices for vagus nerve stimulation. Expert Rev Med Devices. 2018;15(8):527-39. doi: 10.1080/17434440.2018.1507732. Epub 2018 Aug 17.
40. Garamendi-Ruiz I, Gomez-Esteban JC. Cardiovascular autonomic effects of vagus nerve stimulation. Clin Auton Res. 2017;25(10):017-0477.
41. Gassen NC, Hartmann J, Zschocke J, Stepan J, Hafner K, Zellner A, et al. Association of FKBP51 with priming of autophagy pathways and mediation of antidepressant treatment response: evidence in cells, mice, and humans. PLoS Med. 2014;11(11):e1001755.
42. Zschocke J, Zimmermann N, Berning B, Ganal V, Holsboer F, Rein T. Antidepressant drugs diversely affect autophagy pathways in astrocytes and neurons--dissociation from cholesterol homeostasis. Neuropsychopharmacology. 2011;36(8):1754-68.

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Organizational Data

  •   DRKS00016928
  •   2019/03/11
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  •   yes
  •   Approved
  •   024/19, Ethik-Kommission der Medizinischen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn
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Secondary IDs

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Health Condition or Problem studied

  •   F32.2 -  Severe depressive episode without psychotic symptoms
  •   F32.3 -  Severe depressive episode with psychotic symptoms
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Interventions/Observational Groups

  •   Patients with therapy-resitant depression who receive electroconvulsive therapy or vagus nerve stimulation
  •   Patients with therapy-resitant depression who do not receive electroconvulsive therapy or vagus nerve stimulation
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Characteristics

  •   Non-interventional
  •   Observational study
  •   Non-randomized controlled trial
  •   Open (masking not used)
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  •   Active control (effective treament of control group)
  •   Prognosis
  •   Parallel
  •   N/A
  •   N/A
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Primary Outcome

There is no endpoint defined.
The aim of the study is to investigate whether it is possible to predict the effect of the neurostimulation therapy and the course of the disease by measuring heart rate variability, noninvasive determination of autonomic nervous system parameters and assessing laboratory parameters in the blood.

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Secondary Outcome

There is no secondary outcome defined.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
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Recruitment

  •   Planned
  •   2019/05/01
  •   80
  •   Monocenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

• Women and men who meet the criteria for therapy-resistant depression and who have been given the indication for electroconvulsive therapy and / or vagus nerve stimulation
• Age from 18
• Legally valid consent

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Exclusion Criteria

Patients who have a contraindication to electroconvulsive therapy or a contraindication to surgery to implant the Nervus Vagus Stimulator

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Addresses

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    • Klinik für Psychiatrie und PsychotherapieUniversitätsklinikum Bonn
    • Ms.  Prof.  Alexandra  Philipsen 
    • Sigmund-Freud-Str. 25
    • 53127  Bonn
    • Germany
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    • Klinik für Psychiatrie und PsychotherapieUniversitätsklinikum Bonn
    • Mr.  PD Dr.  Helge  Müller 
    • Sigmund-Freud-Str. 25
    • 53127  Bonn
    • Germany
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    • Klinik für Psychiatrie und PsychotherapieUniversitätsklinikum Bonn
    • Mr.  Dr.  Sebastian  Möller 
    • Sigmund-Freud-Str. 25
    • 53127  Bonn
    • Germany
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Sources of Monetary or Material Support

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    • Klinik für Psychiatrie und PsychotherapieUniversitätsklinikum Bonn
    • Ms.  Prof.  Alexandra  Philipsen 
    • Sigmund-Freud-Str. 25
    • 53127  Bonn
    • Germany
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Status

  •   Recruiting planned
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Trial Publications, Results and other Documents

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* This entry means the parameter is not applicable or has not been set.