Invasive vagus nerve stimulation (VNS) is an approved treatment of treatment-resistant depression (TRD) in Europe and in USA. Because of the associated possible surgical complications as well as side effects, invasive VNS is applied limitedly in the treatment of depression. Transcutaneous auricular VNS (tVNS), on the other hand, is a non-invasive alternative to traditional invasive VNS. tVNS is still considered an experimental treatment for depression. This is due to the limited high-quality evidence from randomized clinical studies, the not yet fully understood biological mechanisms of action, along with overall limited knowledge about the optimal stimulation parameters. To address these issues, the AddVNS study was initiated. The AddVNS study intends to recruit n=86 patients of the Max Planck Institute of Psychiatry with depression. The patients participating in the AddVNS study are going to receive either tVNS or sham tVNS for a period of 6 weeks. The primary objective of the study is to identify biological, psychological, socio-economic, and clinical biomarkers associated with treatment progression and response to treatment in patients with depression undergoing tVNS. To achieve this, an exploratory design with an assessment of many different parameters including psychophysiology, imaging, blood-based multi-omics, microbiome, psychometrics and neuropsychology will be used.
Background: Depression is one of the most prevalent mental disorders worldwide and is associated with the highest burden of disease among all psychiatric disorders. Invasive vagus nerve stimulation (VNS) has been approved for the treatment of treatment-resistant depression (TRD). However, invasive VNS is applied limitedly in the treatment of depression due to the associated possible surgical complications and side effects. Transcutaneous auricular VNS (tVNS), on the other hand, is a non-invasive alternative to invasive VNS. During the last decade, the effects of tVNS have been examined in an increasing number of clinical trials across many different disorders, with depression being one of the most prominent areas of interest. Nevertheless, tVNS is still considered an experimental treatment for depression. Reasons for this categorization come from the limited high-quality evidence from randomized clinical studies, the not yet fully understood biological mechanisms of action, along with overall limited knowledge about the optimal stimulation parameters. To address these issues, we initiated the AddVNS study. The primary objective of the study is to identify biomarkers of tVNS and to better understand its biological mechanisms of action in the treatment of depression. Material and methods: The AddVNS is a monocentric, exploratory-prospective, randomized, double-blind, sham-controlled interventional study that recruits adult and legally competent patients with current MDD or bipolar disorder with current depression who are treated in MPIP (either inpatient or day clinic treatment). The participants are going to receive either tVNS or sham tVNS for a period of 6 weeks. Both tVNS and sham tVNS will be carried out as an adjuvant, i.e. in addition to the regular treatment of the participants. The intervention will take place three times a day from Monday to Friday. Each of the three daily sessions is going to last 30-60 minutes, depending on patient tolerance. The procedures for sham tVNS will be identical to tVNS, with the only exception that the sham tVNS will be performed with no current output. Participants and investigators are blinded to the assignment of participants to a study arm, except for the investigators responsible for the stimulation. The AddVNS study includes a wide range of assessments, which will be identical for both study arms. Psychophysiological measurements (pupillometry, respiratory rate, 3-channel ECG, skin conductance level, photoplethysmography and an electrogastrogram) will be conducted at baseline, after 3 weeks of intervention and at the end of the 6-week intervention (for a small number of patients, two additional psychophysiological measurements are planed). Actigraphy will take place throughout the 6-week intervention. Two MRI scans are planned over the course of the AddVNS study; one scan is scheduled at baseline and one after the 6-week intervention. Participants will have a total of three venous blood samples taken over the course of the 6-week intervention. They will be asked to collect stool samples that will be used for microbiome analysis at baseline, after 3 weeks of intervention and at the end of the 6-week intervention. Participants will be also asked to fill out self-rating questionnaires (patient health questionnaire 9 and 15, Beck Depression Inventory II, Snaith-Hamilton-Pleasure-Scale, Questionnaire for complaints of cognitive disturbances) once a week, while two further questionnaires will be obtained at baseline and after the 6-week intervention (Rejection Sensitivity Questionnaire, World Health Organization Disability Assessment Schedule questionnaire). During a clinical interview at baseline, after 3 weeks of intervention and after 6 weeks of intervention, clinician-rating scales (Montgomery-Åsberg Depression Rating Scale, Hamilton Rating Scale for Depression with 21 items, Hamilton Rating Scale for Anxiety, Global Assessment of Functioning) will be obtained. Furthermore, a neuropsychological assessment is carried out at baseline and after the 6-week intervention, while a personality assessment will be performed at baseline. To assess the longitudinal effects of tVNS, we will ask the patients to fill out self-rating questionnaires (patient health questionnaire 9 and 15, Beck Depression Inventory II, Snaith-Hamilton-Pleasure-Scale, Questionnaire for complaints of cognitive disturbances, Rejection Sensitivity Questionnaire, World Health Organization Disability Assessment Schedule questionnaire) 6 and 12 weeks after the end of the intervention. Discussion: Taken together, the main goal of the AddVNS study is to identify biological, psychological, socio-economic, and clinical biomarkers associated with treatment progression and response to treatment in patients with depression undergoing tVNS. The strength of the study lies in its study design, as AddVNS is a randomized controlled trial combining a meticulous documentation of the tVNS procedure with a wide assessment of many different parameters. This makes the AddVNS study one of the most extensive studies of tVNS in depression to date.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
TRIPLE
Enrollment
86
Half of the patients are randomized to the arm receiving transcutaneous auricular vagus nerve stimulation for a period of six weeks. Transcutaneous auricular vagus nerve stimulation will be carried out as an adjuvant, i.e. in addition to the regular treatment of the participants. The intervention will take place three times a day from Monday to Friday. Each of the three daily sessions is going to last 30-60 minutes, depending on patient tolerance.
Half of the patients are randomized to the arm receiving sham transcutaneous auricular vagus nerve stimulation for a period of six weeks. Sham transcutaneous auricular vagus nerve stimulation will be carried out as an adjuvant, i.e. in addition to the regular treatment of the participants. The intervention will take place three times a day from Monday to Friday. Each of the three daily sessions is going to last 30-60 minutes. The procedures for sham tVNS will be identical to tVNS, with the only exception that the sham tVNS will be performed with no current output
Max Planck Institute of Psychiatry
Munich, Germany
RECRUITINGChange from baseline in pupillometry
Pupil diameter associated with the clinical response to tVNS
Time frame: Baseline, week 3, week 6
Change from baseline in 3-channel ECG
3-channel ECG associated with the clinical response to tVNS
Time frame: Baseline, week 3, week 6
Change from baseline in skin conductance level
Skin conductance level associated with the clinical response to tVNS
Time frame: Baseline, week 3, week 6
Change from baseline in photoplethysmography
Photoplethysmography associated with the clinical response to tVNS
Time frame: Baseline, week 3, week 6
Change from baseline in electrogastrogram
Electrogastrogram associated with the clinical response to tVNS
Time frame: Baseline, week 3, week 6
Change from baseline in the functional status of brainstem nuclei
Functional status of selected brainstem nuclei (by fMRI) associated with the clinical response to tVNS
Time frame: Baseline, week 6
Change from baseline in the response patterns in the reward anticipation task
Response patterns in the reward anticipation task (by fMRI) with the clinical response to tVNS
Time frame: Baseline, week 6
Change from baseline in motor activity
Motor activity changes, measured by actigraph, associated with the clinical response to tVNS
Time frame: Continuously starting from baseline up to week 6
Change from baseline in heart rate
Heart rate, measured by actigraph, associated with the clinical response to tVNS
Time frame: Continuously starting from baseline up to week 6
Change from baseline in heart rate variability
Heart rate variability, measured by actigraph, associated with the clinical response to tVNS
Time frame: Continuously starting from baseline up to week 6
Change from baseline in oxygen saturation
Oxygen saturation, measured by actigraph, associated with the clinical response to tVNS
Time frame: Continuously starting from baseline up to week 6
Change from baseline in skin temperature
Skin temperature, measured by actigraph, associated with the clinical response to tVNS
Time frame: Continuously starting from baseline up to week 6
Investigation of gene expression changes
Gene expression changes over time (based on material extracted from peripheral blood)
Time frame: Baseline, week 3, week 6
Investigation of epigenetic changes
Epigenetic changes over time (based on material extracted from peripheral blood)
Time frame: Baseline, week 3, week 6
Investigation of protein changes
Protein changes over time (based on material extracted from peripheral blood)
Time frame: Baseline, week 3, week 6
Investigation of lipid changes
Lipid changes over time (based on material extracted from peripheral blood)
Time frame: Baseline, week 3, week 6
Investigation of electrolyte changes
Electrolyte changes over time (based on material extracted from peripheral blood)
Time frame: Baseline, week 3, week 6
Investigation of immunophenotypic changes
Immunophenotypic changes over time (based on material extracted from peripheral blood)
Time frame: Baseline, week 3, week 6
Microbiome changes
Microbiome changes (bacteria strains and metabolites) over time
Time frame: Baseline, week 3, week 6
Genetics
Genotyping based on material extracted from peripheral blood
Time frame: Baseline
Change from baseline in the Hamilton Depression Rating Scale (HAM-D)
The HAM-D measures the presence and severity of depression. Each of the items is rated by a study clinician or trained study staff member and added up to a summary score. Treatment response is generally defined by 50% score reduction, while remission is commonly assumed if the HAM-D score is ≤ 7 points
Time frame: Baseline, week 3, week 6
Change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS)
The MADRS measures the presence and severity of depression. Each of the terms is rated by a study clinician or trained study staff member and added up to a summary score. Treatment response is generally defined by 50% score reduction, while remission is commonly assumed if the MADRS score falls short of 12 points
Time frame: Baseline, week 3, week 6
Change from baseline in the Global Assessment of Functioning (GAF)
The GAF approximates the level of symptom burden and psychosocial as well as occupational functioning in daily life. It is tailored primarily to psychiatric patients. It is rated from 0 to 100 by a trained clinician. The GAF score is a continuous variable and allows to estimate symptom reduction and functional assessment from a foreign rater perspective
Time frame: Baseline, week 3, week 6
Change from baseline in the Beck-Depression-Inventory II (BDI-II)
The BDI-II measures the presence and severity of depression symptoms on a mostly psychological and partially somatic level. Each of the 21 items is rated by the patient and added up to a summary score. Treatment response is generally defined by 50% score reduction, while remission is commonly assumed if the BDI-II score is ≤ 10 points
Time frame: Weekly up to week 6, week 12, week 18
Change from baseline in the Patient Health Questionnaire 9 (PHQ-9)
The PHQ-9 is a brief measure of depression symptoms. Each of the 9 items is rated by the patient from 0 = not at all to 3 = nearly every day and added up to a summary score. Treatment response is generally defined by 50% score reduction, while remission is commonly assumed if the PHQ-9 score is ≤ 5 points.
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Time frame: Weekly up to week 6, week 12, week 18
Change from baseline in the Patient Health Questionnaire 15 (PHQ-15)
The PHQ-15 is a measure of somatic symptom load in psychiatric disorders. Each of the 15 somatic symptoms is rated by the patient from 0 = not affected to 2 = strongly affected and added up to a summary score. Cut-off values are ≥ 5points (mild), ≥ 10 points (moderate), ≥ 15 points (severe) and represent somatization.
Time frame: Weekly up to week 6, week 12, week 18
Change from baseline in the Questionnaire on Mental Capacity (FLEI = Questionnaire for Complaints of Cognitive Disturbances )
The FLEI measures neurocognitive functioning in the following domains: attention, memory, executive function, control scale. Each of the 35 questions is answered by the patient from 0 = never to 4 = very often. Summary scores are computed for the different neurocognitive domains. Since the FLEI is primarily a continuous variable, symptom reduction is commonly assessed quantitatively
Time frame: Weekly up to week 6, week 12, week 18
Change from baseline in the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0.) questionnaire
The WHODAS 2.0. questionnaire is a self-rating instrument with 36 items for the assessment of health, functioning, disability and health-related quality of life which can be used across all diseases
Time frame: Baseline, week 6, week 12, week 18
Change from baseline in the Rejection Sensitivity Questionnaire (RSQ)
The German modified version of RSQ with 20 items will be used as a measure of rejection sensitivity (RS) to explore the role of RS in the context of tVNS in depressive disorders.
Time frame: Baseline, week 6, week 12, week 18
Change from baseline in Snaith-Hamilton-Pleasure-Scale (SHAPS-D)
SHAPS-D is an instrument for the assessment of anhedonia. Each of the 14 items is rated by the patient and added up to a summary score. Anhedonia is commonly assumed if the SHAPS-D score is \> 2.
Time frame: Weekly up to week 6, week 12, week 18
Change from baseline in Hamilton Rating Scale for Anixety (HAM-A)
HAM-A is a rating scale for the assessment of anxiety symptoms. Each of the 14 items is rated by a study clinician or trained study staff and added up to a summary score with a total range from 0 to 56. Remission of anxiety is commonly assumed if the HAM-A score is ≤ 7.
Time frame: Baseline, week 3, week 6
Change from baseline in Trail Making Test Version A (TMT-A) and B (TMT-B)
TMT is an attention test from COGBAT basic cognitive testing. In the A version, the patient is given the task of connecting circles with the numbers 1 to 25 as quickly as possible in ascending order. This is followed by the B version of the test, in which the patient has to connect circles with the numbers from 1 to 13 and letters from A to L alternatingly in ascending order.
Time frame: Baseline, week 6
Change from baseline in TOL-F test (Tower of London - Freiburg version)
TOL-F is a test for planning ability from COGBAT basic cognitive testing. In this task, the patient must move balls on wooden sticks in the fewest number of moves possible so that the specified target condition is reached.
Time frame: Baseline, week 6
Change from baseline in Episodic memory test
A short text is read aloud and the patient is asked to memorize the content. The patient is asked to repeat the text immediately after it has been read aloud and again after 30 minutes.
Time frame: Baseline, week 6
Change from baseline in the INHIB test (Response inhibition)
INHIB is a test for response inhibition from the COGBAT basic cognitive testing. In this task, circles and triangles are preset. Whenever the triangle appears, the patient must press a button as quickly as possible (go trial), ignoring the circles (no-go trial).
Time frame: Baseline, week 6
Change from baseline in N-back-verbal test (NBV)
N-back is a test for working memory from COGBAT basic cognitive testing. The patient is presented with a sequence of letters on a screen and should press a button when the presented letter is the same as the letter before.
Time frame: Baseline, week 6
Change from baseline in WAF test (perception and attention functions battery )
WAF is a test baterry for the assessment of sub-functions of attention and is part of the COGBAT basic cognitive testing. In the AddVNS study the test for cross-modal visual /auditory attention and the test for intrinsic (visual) alertness are used. In the task for cross-modal visual/auditory attention, the patient concentrates simultaneously on a figure and on an auditory stimulus. The intensity of the stimuli changes at certain intervals. The patient must react as soon as one of the two stimuli becomes brighter or quieter twice in a row. In the task for intrinsic (visual) alertness, the patient has to press a button as quickly as possible as soon as a black circle appears on the screen.
Time frame: Baseline, week 6
Change from baseline in MWT-B test (multiple-choice vocabulary intelligence test B )
MWT-B is a multiple choice vocabulary intelligence test. In this test, the patient is given 37 rows with five words each, only one of which actually exists and should be crossed out accordingly.
Time frame: Baseline, week 6