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The primary objective of this study is to assess short, mid and long-term clinical outcomes in patients with difficult to treat depression (such as patients with treatment resistant depression) treated with Vagus Nerve Stimulation (VNS) Therapy as adjunctive therapy.
The population under study comprises a real-world patient population with difficult to treat depression: patients diagnosed with unipolar or bipolar disorder with chronic or recurrent depression who fail to achieve an adequate response to standard psychiatric management.
The diagnosis of depression and comorbid disorders will be determined based on the Mini International Neuropsychiatric Interview (MINI).
A minimum of five hundred (500) patients will be implanted with a VNS Therapy System and up to eighty (80) sites may participate in this study.
Enrollment will take 8 years, based on competitive enrollment. For each subject a baseline visit will occur between 1 and 6 weeks before implant.
Once implanted with the device, subjects will be followed-up for a minimum of 36 months and a maximum of 60 months. The study may stop when the last subject has reached the 36 months follow-up.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Vagal Nerve Simulation (VNS) Therapy | The aim of this study is to include patients with difficult to treat depression from a global "real world" (standard of care) population who are referred for treatment with VNS Therapy. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Vagal Nerve Simulation (VNS) Therapy | Device | A VNS Therapy System used for vagus nerve stimulation and consisting of an implantable VNS Therapy generator, lead, and external programming system. |
| Measure | Description | Time Frame |
|---|---|---|
| The primary endpoint of this study is response defined as reduction in Montgomery Åsberg Depression Rating Scale (MADRS) total score of at least 50% from baseline to 12 months post implant. | MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. Each item yields a score of 0 to 6. The overall score ranges from 0 to 60. Higher MADRS score indicates more severe depression. A 'Responder' is a subject that achieved ≥ 50% reduction from baseline in MADRS total score at the M12 assessment. A 'Non-Responder' is any patient who did not achieve ≥ 50% reduction from baseline in MADRS score at the M12 assessment. No formal hypothesis testing is presented; all the proposed statistical tests are descriptive in nature. The Primary endpoint analysis as defined above will be done only on patients that are enrolled while in a major depressive episode (MDE); the cut off point for current MDE at time of implant will be a MADRS score of 20. For the patients with a MADRS score below 20 at time of enrollment, only the continuous change in MADRS can be described (as the MADRS can only worsen or stay the same). | 12 months |
| Measure | Description | Time Frame |
|---|---|---|
| Duration of response | computed as the difference between the first recorded date post baseline that response is achieved (MADRS reduction from baseline ≥ 50%) and the first date at which MADRS again increased to a level of <40% from baseline. | through study completion, an average of 4 years |
| Change in MADRS |
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Inclusion Criteria:
Exclusion Criteria:
There are no exclusion criteria; the investigator should refer to the (local applicable) VNS Therapy Physician's Manual.
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The population under study comprises a real-world patient population with difficult to treat depression: patients diagnosed with unipolar or bipolar disorder with chronic or recurrent depression who fail to achieve an adequate response to standard psychiatric management.
The diagnosis of depression and comorbid disorders will be determined based on the Mini International Neuropsychiatric Interview (MINI).
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Funda Basdar | Contact | +32 473 97 49 41 | funda.basdar@livanova.com | |
| Gaia Giannicola | Contact | Gaia.Giannicola@livanova.com |
| Name | Affiliation | Role |
|---|---|---|
| Koen Demyttenaere, Prof. | KU Leuven | Principal Investigator |
| Allan Young, Prof. | King's College | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| AKH Allgemeines Krankenhaus der Stadt Wien | Recruiting | Vienna | 1090 | Austria |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40021060 | Derived | Kavakbasi E, Kraus C, Reif-Leonhard C, Blackwell JM, Dibue M, Treiber M, Achten S, Baune BT. Titration of vagus nerve stimulation for difficult-to-treat depression and onset of response: Early insights from the RESTORE-LIFE study. J Affect Disord. 2025 Jun 1;378:39-46. doi: 10.1016/j.jad.2025.02.047. Epub 2025 Feb 26. | |
| 38340111 |
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Change in MADRS over time |
| through study completion, an average of 4 years |
| Cumulative response | Cumulative percentage of first-time MADRS responders (MADRS reduction from baseline ≥ 50%) at any post-baseline visit. | through study completion, an average of 4 years |
| Cumulative remission | Cumulative percentage of subjects in remission (MADRS ≤9) at any post-baseline visit. | through study completion, an average of 4 years |
| Changes in depression score As measured by the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR). | The Quick Inventory of Depressive Symptomatology (QIDS-SR) is a 16-item, subject-completed questionnaire of the symptoms of mood and depression. The total score ranges from 0 to 27. A higher QIDS-SR score indicates a more severe depression. | through study completion, an average of 4 years |
| Changes in mania score as measured by the Altman Self-Rating Mania Scale (ASRM)*. | *Optional assessments: to be done at selected sites only and based on investigator's clinical judgment to decide which subjects complete them. The Altman Self-rating Mania Scale (ASRM) is a 5-item self-reported diagnostic scale which can be used to assess the presence and severity manic and hypomanic symptoms, most commonly in patients diagnosed with bipolar disorder. The total score ranges from 0 to 20. A score of 6 or higher indicates a high probability of a manic or hypomanic condition. | through study completion, an average of 4 years |
| Changes in Quality of Life as measured by the EuroQol five dimensions questionnaire (EQ-5D-5L) | The EuroQol five dimensions questionnaire (EQ-5D-5L) is a standardized 5-item subject completed questionnaire measuring generic health status and quality of life. | through study completion, an average of 4 years |
| Changes in patient function as measured by the Work Productivity and Activity Impairment Scale (WPAI) | The Work Productivity and Activity Impairment Questionnaire (WPAI) is a subject self-reported 6-item questionnaire that measures impairments in work and activities. WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity. | through study completion, an average of 4 years |
| Changes in Quality of Life and patient function as measured by the Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF) | The Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF) is a standardized 16-item, self-report scale to assess the degree of enjoyment and satisfaction experienced by the subject during the past week. | through study completion, an average of 4 years |
| Changes in suicidality as measured by item #10 of MADRS. | Item 10 on the Montgomery-Åsberg Depression Rating Scale (MADRS) scale assesses suicidal thoughts as representing the feeling that life is not worth living, that a natural death would be welcome, suicidal thoughts and preparations for suicide and is rated from 0 to 6. A score of ≥ 4 ('probably better off dead') is of particular interest. | through study completion, an average of 4 years |
| Changes in suicidality as measured by item #12 of QIDS-SR. | For Item 12 of the Quick Inventory of Depressive Symptomatology (QIDS-SR), the subject assesses any thoughts of death or suicide over the previous 7 days on a 4- point scale; a score of ≥ 2 ('I think of suicide or death several times a week for several minutes') being of interest. | through study completion, an average of 4 years |
| Changes in adjunctive antidepressant pharmacological treatment | All adjunctive concomitant antidepressant and psychotropic medications will be collected | through study completion, an average of 4 years |
| Changes in adjunctive antidepressant non-pharmacological treatment | The following adjunctive non-pharmacological treatments will be collected: maintenance electroconvulsive therapy (ECT), Transcranial Magnetic Stimulation (TMS) and psychotherapy | through study completion, an average of 4 years |
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | The following adverse events will be collected: serious adverse events, deaths, VNS Therapy related adverse events and device deficiencies. | through study completion, an average of 4 years |
| Changes in cognition | As measured by THINC-it® Tool*. *Optional assessments: to be done at selected sites only and based on investigator's clinical judgment to decide which subjects complete them. | through study completion, an average of 4 years |
| Changes in anxiety as measured by the Generalized Anxiety Disorder Assessment (GAD 7)*. | *Optional assessments: to be done at selected sites only and based on investigator's clinical judgment to decide which subjects complete them. The Generalized Anxiety Disorder 7 (GAD-7) is a 7-item self-reported questionnaire for screening and severity measuring of generalized anxiety disorder (GAD). GAD-7 has seven items and uses a normative system of scoring. Assessment is indicated by the total score, which made up by adding together the scores for the scale all seven items. | through study completion, an average of 4 years |
| KU Leuven | Recruiting | Leuven | Belgium |
|
| Sozialstiftung Bamberg - Klinikum am Bruderwald | Withdrawn | Bamberg | Germany |
| Universitätsklinikum Bonn | Recruiting | Bonn | Germany |
|
| Universitätsklinikum Köln | Recruiting | Cologne | Germany |
|
| LVR-Hospital Essen | Recruiting | Essen | 45147 | Germany |
|
| Universitätsklinikum Frankfurt | Recruiting | Frankfurt | Germany |
|
| Universitätsklinikum Freiburg | Completed | Freiburg im Breisgau | Germany |
| Universitätsmedizin Göttingen | Withdrawn | Göttingen | Germany |
| Medizinische Hochschule Hannover | Withdrawn | Hanover | Germany |
| Universitätsklinikum Jena | Completed | Jena | Germany |
| Universitätsklinik Leipzig | Recruiting | Leipzig | 04103 | Germany |
|
| University Hospital Münster | Recruiting | Münster | Germany |
|
| Klinikum Wilhelmshaven | Active, not recruiting | Wilhelmshaven | Germany |
| Glenfield hospital | Recruiting | Leicester | LE3 9EJ | United Kingdom |
|
| King's College London | Recruiting | London | United Kingdom |
|
| Academic Psychiatry Wolfson Research Centre | Recruiting | Newcastle upon Tyne | United Kingdom |
|
| Mendip HTT / St Andrew's Ward | Active, not recruiting | Wells | BA5 1TH | United Kingdom |
| Kavakbasi E, Baune BT. Combination of Acute and Maintenance Esketamine Treatment With Adjunctive Long-Term Vagus Nerve Stimulation in Difficult-to-Treat Depression. Neuromodulation. 2024 Jun;27(4):766-773. doi: 10.1016/j.neurom.2023.12.004. Epub 2024 Feb 10. |
| 38194603 | Derived | Kavakbasi E, Rosemann K, Yilmaz M, Vasileiadou A, Falcone V, Baune BT. Vagus Nerve Stimulation Combined With Alternating Synchronized and Nonsynchronized Intermittent Theta Burst Stimulation in Difficult-to-Treat Depression. J ECT. 2024 Mar 1;40(1):62-63. doi: 10.1097/YCT.0000000000000964. Epub 2023 Dec 28. No abstract available. |
| 32993573 | Derived | Young AH, Juruena MF, De Zwaef R, Demyttenaere K. Vagus nerve stimulation as adjunctive therapy in patients with difficult-to-treat depression (RESTORE-LIFE): study protocol design and rationale of a real-world post-market study. BMC Psychiatry. 2020 Sep 29;20(1):471. doi: 10.1186/s12888-020-02869-6. |
| ID | Term |
|---|---|
| D061218 | Depressive Disorder, Treatment-Resistant |
| ID | Term |
|---|---|
| D003866 | Depressive Disorder |
| D019964 | Mood Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| D013812 | Therapeutics |
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