Clinical trial NCT05952674: Treatment Resistant Depression and Vagus Nerve Stimulation
Official title: Resistant Depression and Vagus Nerve Stimulation : a Medico-economic, Multicenter, Randomized and Open Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Treatment Resistant Depression (TRD)
Keywords: Treatment Resistant Depression (TRD)
Vagus Nerve Stimulation (VNS)
Best Medical Treatment (BMT)
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: LivaNova
First posted: 2023-07-19
Enrollment: 166
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients (166) suffering from resistant depression will be enrolled over a 24-month period and will be randomized in a (1:1) ratio to receive either Vagus Nerve Stimulation (VNS) along with the Best Medical Treatment (VNS+BMT arm) or the Best Medical Treatment only (BMT arm).
Primary purpose: TREATMENT

Brief summary: Depression is a common illness, affecting 17% of the population over the course of a lifetime. A third of depressions relapses and progresses to recurrence and resistance to treatments. Despite the optimization of antidepressant medical strategies, 20 to 40% of depressions do not respond to treatment. This is particularly worrying as 6% of non-responder patients will die by committing suicide.

Depression has a major impact on quality of life, socio-professional functioning and healthcare consumption.

Sometimes, TRD is part of a bipolar illness. In this case, the challenge is even bigger because antidepressants are no well tolerated, further reducing the therapeutic options in case of resistance, the severity and duration of the depressive episodes are the main factors explaining the deterioration of the quality of life and the increasing cost of cares for these patients.

The standard treatment for TRD is electroconvulsive therapy (ECT), which results in a response in 60 to 70% of cases after a few weeks of treatment. However, the improvement is often transient and 40% of patients relapse within 6 months of the initial ECT session. Moreover, ECT is often not well tolerated. This therapeutic impasse therefore makes TRD a priority public health target to which it is urgent to provide a realistic medico-economical response.

The literature suggests that Vagus Nerve Stimulation (VNS) has unique kinetics of efficacy in depression, particularly in preventing long-term recurrences, and therefore responding to the lack of effective maintenance treatment in TRD. In fact, the benefits of VNS gradually accumulate over 12-24 months, which makes it complementary to more incisive treatments like ECT. Finally, its efficacy-tolerance profile appears to be similar in uni and bipolar TRD, giving VNS a potentially unique place in the therapeutic arsenal in psychiatry.

The DepVNS hypothesis is that VNS is a medico-economically efficient therapeutic option to overcome the therapeutic impasse in which patients suffering from uni and bipolar DR currently find themselves due to the frequency of relapses under treatment.

The primary objective is to estimate, from a collective point of view, the incremental cost-utility ratio of VNS to treat patients suffering from RD.

Detailed description: Depression is a common illness, affecting 17% of the population over the course of a lifetime. A third of depressions relapses and progresses to recurrence and resistance to treatments. Despite the optimization of antidepressant medical strategies, 20 to 40% of depressions do not respond to treatment. This is particularly worrying as 6% of non-responder patients will die by committing suicide. The term treatment-resistant depression (TRD) is used when two or more (and often many more) well conducted antidepressant treatments from different classes have failed to achieve remission.

Depression has a major impact on quality of life, socio-professional functioning and healthcare consumption. According to the World Health Organization (WHO), depression will be the second cause of healthcare costs in the world by 2020. RD alone accounts for 30 to 40% of the annual cost of depression.

Sometimes, TRD is part of a bipolar illness, a psychiatric condition characterized by the alternation of depressive and maniac episodes that affects 4% of the population. In this case, the challenge is even bigger because (1) antidepressants are no well tolerated, further reducing the therapeutic options in case of resistance, (2) the severity and duration of the depressive episodes are the main factors explaining the deterioration of the quality of life and the increasing cost of cares for these patients. Bipolar RD currently accounts for 20% of all psychiatric spending.

The standard treatment for TRD is electroconvulsive therapy (ECT), which results in a response in 60 to 70% of cases after a few weeks of treatment. However, the improvement is often transient and 40% of patients relapse within 6 months of the initial ECT session. Moreover, ECT is often not well tolerated because of the frequency and the intensity of the memory disorders associated, the repetition of anesthesia and hospitalizations and its social stigma. Refusals and requests to stop ECT are therefore common even when it is effective, as these constraints are sometimes experienced as being unbearable in the long-term. This therapeutic impasse therefore makes TRD a priority public health target to which it is urgent to provide a realistic medico-economical response.

The literature suggests that Vagus Nerve Stimulation (VNS) has unique kinetics of efficacy in depression, particularly in preventing the long-term recurrences, and therefore responding to the lack of effective maintenance treatment in TRD. In fact, the benefits of VNS gradually accumulate over 12-24 months, which makes it complementary to more incisive treatments like ECT. Finally, its efficacy-tolerance profile appears to be similar in uni and bipolar TRD, giving VNS a potentially unique place in the therapeutic arsenal in psychiatry. VNS has been approved for over 15 years as a treatment for RD in the Unites States and Great-Britain.

The hypothesis is that VNS is a medico-economically efficient therapeutic option to overcome the therapeutic impasse in which patients suffering from uni and bipolar DR currently find themselves due to the frequency of relapses under treatment.

The primary objective is to estimate, from a collective point of view, the incremental cost-utility ratio of VNS to treat patients suffering from RD.

The secondary objectives are evaluating the efficacy and the security of the VNS, as well as positioning the VNS in comparison with ECT that is currently the standard treatment for TRD.

This is a national multicenter comparative, open, randomized, controlled, two-parallel group clinical trial evaluating the medico-economic impact of VNS in resistant depression population. Patients (166) suffering from resistant depression will be enrolled over a 24-month period and will be randomized in a (1:1) ratio to receive either Vagus Nerve Stimulation (VNS) along with the Best Medical Treatment (VNS+BMT arm) or the Optimal Medical Treatment only (BMT arm).

Patients meeting all eligibility criteria will be enrolled in the study.

All subjects will be followed by the investigators or designee of the investigator during the whole study period by visits on site.

Number of visits/participant: Both arms will attend: selection visit (VS), inclusion visit (VI) and randomization visit (R), M0, M2, M4, M6, M8, M10, M12, M14, M16, M18, M20, M22 and M24. After the inclusion visit, the experimental arm (VNS + BMT) will further attend a neurosurgical and anesthetic consultation before being hospitalized for the VNS system placement. The patient will finally be hospitalized in psychiatry for about 5 days for switching the device on. If the target intensity has not been reached during this hospitalization, an adjustment visit is planned every month for 6 months in order to progressively increase the stimulation intensity until the target or a therapeutic response. If the target or the therapeutic response is obtained, the settings adjustments rhythm will be at the indiscretion of the psychiatrist. If at the end of the 6 first visits (M1 to M6), the target intensity couldn't be reached or in absence of a satisfying clinical response, a visit will be planned every 3 months (consultation or hospitalization) to keep optimizing the VNS.

Eligibility criteria: Inclusion Criteria:

* Patients aged 18 years and older ;
* Childbearing women must have an efficient contraception for the whole study period
* Diagnosis of recurrent depressive trouble or persistent depressive disorder or bipolar disorder (according to DSM-5)
* Start of disorder (defined by the occurrence of the first thymus episode: characterized depressive disorder or maniac episode with or without mixed characteristics) for 5 years or more
* At least one of the following criteria:

  * Criterion A: current characterized depressive disorder and characterized depressive disorder for at least 12 months during the last 24 months despite at least four treatments lines at appropriate dosage and duration
  * Criterion B: current treatment by ECT and criteria A before the start of the ECT treatment or ECT dependency criteria
* Patients who, after the nature of the study has been explained to them, have given written consent

Exclusion Criteria:

* Know pregnancy or breastfeeding
* Schizophrenia, schizoaffective disorder or persistent delusional disorder (DSM-5)
* Characterized depressive disorder with psychotic characteristics within 3 months before the inclusion (DSM-5)
* Concomitant participation to another interventional clinical trial, excepted eventual ancillary researches validated by the study scientific committee. Participation to non-interventional researches is allowed.
* Patients receiving enforced cares (ASPDT, ASPPI, ASPDRE, etc.)
* Non-affiliation to a social security regimen or any other social protection regimen
* Disability, according to the investigator, to understand the study or refusal to sign the study consent form (non-francophone patient, cognitive disorders)
* Anticipated disability to attend all the visits, treatments and measures planned by the protocol: severe personality disorder, severe substance addiction, severe intellectual development disorder. In any of those cases, the notion of severity is at the indiscretion of the investigator

Secondary Exclusion Criteria:

* Surgical contraindication to the VNS
* Positive β-HCG (results obtained after the informed consent is signed but before the randomization)

Primary outcomes:
measure: Cost-utility of VNS
timeFrame: Month 24
Secondary outcomes:
measure: Efficacy of the VNS
timeFrame: Month 24
measure: Efficacy of the VNS
timeFrame: Month 24
measure: Efficacy of the VNS
timeFrame: Month 24
measure: Efficacy of the VNS
timeFrame: Month 24
measure: Efficacy of the VNS
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Efficacy of the VNS
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Efficacy of the VNS
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Efficacy of the VNS
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Efficacy of the VNS
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Efficacy of the VNS
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Efficacy of the VNS
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Efficacy of the VNS
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Efficacy of the VNS
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Efficacy of the VNS
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Efficacy of the VNS
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Efficacy of the VNS
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Efficacy of the VNS
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Efficacy of the VNS
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Efficacy of the VNS
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Efficacy of the VNS
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Efficacy of the VNS
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Efficacy of the VNS
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Efficacy of the VNS
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Efficacy of the VNS
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Efficacy of the VNS
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Efficacy of the VNS
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Efficacy of the VNS
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Efficacy of the VNS
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Impact of the VNS on ECT (electroconvulsive therapy)
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Impact of the VNS on ECT (electroconvulsive therapy)
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Impact of the VNS on ECT (electroconvulsive therapy)
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Impact of the VNS on ECT (electroconvulsive therapy)
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Impact of the VNS on ECT (electroconvulsive therapy)
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Impact of the VNS on ECT (electroconvulsive therapy)
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Impact of the VNS on ECT (electroconvulsive therapy)
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
measure: Impact of the VNS on ECT (electroconvulsive therapy)
timeFrame: Months: 0, 12, 24
measure: Security of the VNS
timeFrame: Months: 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24
Other outcomes:
Locations:
city: Angers
country: France
facility: CHU Angers
city: Bordeaux
country: France
facility: Centre Hospitalier Charles Perrens
city: Caen
country: France
facility: CHU Caen
city: Clermont-Ferrand
country: France
facility: CHU Clermont-Ferrand, Hôpital Gabriel Montpied
city: Colombes
country: France
facility: AP-HP. Nord - Université de Paris, Hôpital Louis Mourier
city: Créteil
country: France
facility: APHP. Hôpitaux Universitaires Henri Mondor, Hôpital Henri Mondor
city: Dijon
country: France
facility: CHU Dijon, Hôpital Le Bocage
city: Grenoble
country: France
facility: CHU Grenoble Alpes
city: Issy les Moulineaux
country: France
facility: AP-HP. Centre - Université de Paris, Hôpital Corentin-Celton
city: Le Kremlin-Bicêtre
country: France
facility: AP-HP. Université Paris Saclay, Hôpital Bicêtre
city: Lille
country: France
facility: CHU Lille
city: Lyon
country: France
facility: Hospices Civils de Lyon, Hôpital Pierre Wertheimer
city: Marseille
country: France
facility: Assistance Publique Hôpitaux de Marseille, Hôpital de la Conception
city: Nantes
country: France
facility: CHU de Nantes, Hôtel Dieu
city: Nice
country: France
facility: CHU Nice, Hôpital Pasteur 1
city: Paris
country: France
facility: AP-HP. Sorbonne Université, Hôpital La Pitié Salpetrière
city: Paris
country: France
facility: GHU Paris Psychiatrie & Neuroscience, site Saint Anne
city: Poitiers
country: France
facility: Centre Hospitalier Henri Laborit
city: Rennes
country: France
facility: Centre Hospitalier Guillaume Regnier
city: Rouen
country: France
facility: CHU Rouen, Centre Hospitalier du Rouvray
city: Saint-Etienne
country: France
facility: CHU Saint-Etienne
city: Toulouse
country: France
facility: CHU Toulouse, Hôpital de Psychiatrie
city: Tours
country: France
facility: CHRU Tours, Clinique Psychiatrique Universitaire
Study officials:
affiliation: GHU Paris Psychiatrie & Neurosciences (site Sainte-Anne)
name: Philippe DOMENECH, MD, MSc
role: STUDY_DIRECTOR
References: