A Study to Assess Effectiveness and Efficiency of VNS Therapy in Patients With Difficult to Treat Depression.

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).

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.

Change in MADRS over time

Cumulative percentage of first-time MADRS responders (MADRS reduction from baseline ≥ 50%) at any post-baseline visit.

Cumulative percentage of subjects in remission (MADRS ≤9) at any post-baseline visit.

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.

*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.

The EuroQol five dimensions questionnaire (EQ-5D-5L) is a standardized 5-item subject completed questionnaire measuring generic health status and quality of life.

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.

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.

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.

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.

All adjunctive concomitant antidepressant and psychotropic medications will be collected

The following adjunctive non-pharmacological treatments will be collected: maintenance electroconvulsive therapy (ECT), Transcranial Magnetic Stimulation (TMS) and psychotherapy

The following adverse events will be collected: serious adverse events, deaths, VNS Therapy related adverse events and device deficiencies.

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.

*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.