Efficacy and Biomarkers of Response of TBS in Treatment Resistant Depression

Study Overview
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Brief Summary
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Theta Burst Transcranial Magnetic Stimulation (TBS) in dorsolateral prefrontal cortex (DLPFC) has shown efficacy and safety as an adjuvant strategy for resistant to treatment depression (RTD) in daily sessions during 4-6 weeks (20-30 sessions). Current investigation in TBS aims to design intensive treatment protocols so as to achieve earlier responses and higher rates of efficacy. However, the implementation of TBS in the Public National Health Service requires cost-effective protocols that ensure and facilitate patients adherence to treatment, and whose design is based on clinical and neuroimaging biomarkers of response so as to adequately select candidate patients. The aim of this study is to assess the efficacy and safety of novel bilateral and unilateral intensive and spaced protocols of TBS in outpatients with unipolar and bipolar RTD compared with sham stimulation. Specific objectives: I) Comparison of mood change, response and remission of depressive illness at the end of TBS protocol in the groups and maintenance of its effect at 3 months; II) Characterization of neuroimaging cerebral connectivity networks and cerebral metabolism patterns of patients with RTD related to the effects of bilateral or unilateral TBS; III) Identification of clinical and demographic predictors contributing to response to TBS; IV) Analysis of the interaction between clinical, demographic and neuroimaging predictors so as to determine a RTD profile of patient that can benefit from TBS.

Detailed Description
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Participants will receive 22 bilateral sessions of sham/active continuous (right DLPFC) and intermittent (left DLPFC) TBS during 6 weeks. Simultaneous cerebral PET-MRI will be performed before (week 0) and after the treatment with TBS (week 7) Weeks 1 and 2: 1 session 5 days a week (10 sessions) Weeks 3,4,5, 6: 1 session 3 days a week (12 sessions)

Official Title
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Efficacy, Clinical and Neuroimaging Biomarkers of Response of Two Intensive/Spaced Protocols of Theta-Burst Transcranial Magnetic Stimulation in Resistant Depression: a Randomized Double-blinded Placebo-controlled Clinical Trial

Conditions
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Resistant Depression, Treatment, Bipolar Depression

Intervention / Treatment
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* Device: Theta Burst Transcranial Magnetic Bilateral Stimulation
* Device: Theta Burst Transcranial Magnetic Sham Stimulation
* Device: Theta Burst Transcranial Magnetic Unilateral Stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Major Depressive Episode or Depressive phase in Bipolar Disorder DSM-5 criteria. Moderate severity (>14 points in HDRS) 2 antidepressant failures or failure in enhancing strategies in the case of bipolar depression. No changes in treatment 3 week previous to the onset of treatment with TMS. Ability to sign informed consent. Exclusion Criteria: Any psychiatric comorbidity in axis I or II. Depressive episode with psychotic features. Dysthymia. Treatment with ECT in current depressive episode. Multiresistance (> 6 trials of therapeutic strategies). Suicide risk assessed previous to each session. Patients who miss 2 TMS sessions in a row Neurological comorbidities (epilepsy, Parkinson disease, neurocognitive disorders). Contraindications to TMS: pregnancy, metallic cervical or head implants.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group Bilateral<br>32 patients, bilateral active TBS stimulation, Will receive an intensive-spaced protocol Intermittent TBS in left DLPFC and Continuous TBS in right DLPFC | Device: Theta Burst Transcranial Magnetic Bilateral Stimulation<br>* TMS protocol of 22 sessions of bilateral active 1800 pulses.<br>|
| Active Comparator: Group Unilateral<br>32 patients, unilateral left DLPFC active TBS stimulation. Will receive an intensive-spaced protocol Intermittent TBS in left DLPFC and Sham Continuous TBS in right DLPFC | Device: Theta Burst Transcranial Magnetic Unilateral Stimulation<br>* TMS protocol of 22 sessions of left active 1800 pulses and right sham 1800 pulses.<br>|
| Placebo Comparator: Group Placebo<br>32 patients, bilateral sham TBS stimulation. Will receive an intensive-spaced protocol of Sham Intermittent TBS in left DLPFC and Sham Continuous TBS in right DLPFC | Device: Theta Burst Transcranial Magnetic Sham Stimulation<br>* TMS protocol of 22 sessions of sham bilateral 1800 pulses.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hamilton Depression Rating Scale 17 items (HDRS-17) at the end of the treatment respect to basal. | Hetero-administered | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Beck Depression Inventory (BDI-II) respect to basal. | Self-administered | 2, 6 weeks | 
| Montgomery Asberg Depression Rating Scale (MADRS) respect to basal. | Hetero-administered | 2, 6 weeks | 
| Young Mania Rating Scale (YMRS) at the end of the treatment respect to basal. | Hetero-administered | 2, 6 weeks | 
| Altman Self Rating Mania Scale (ASRM) at the end of the treatment respect to basal. | Self-administered | 2, 6 weeks | 
| Clinical Global Impression Scale (CGI) respect to basal. | Hetero-administered | 2,6 weeks | 
| Hamilton Anxiety Scale (HAM-A) respect to basal. | Hetero-administered | 2,6 weeks | 
| Oviedo Sleep Questionnaire (OSQ) respect to basal. | Hetero-administered | 2, 6 weeks | 
| Dimensional Apathy Scale (DAS) respect to basal | Self-administered | 6 weeks | 
| Screening for Cognitive Impairment por Psychiatry (SCIP) at the end of the treatment respect to basal. | Hetero-administered (versions A and B) | 6 weeks | 
| Short Form Health Survey (SF 36) at the end of the treatment respect to basal. | Self-administered | 6 weeks | 
| Functional Assessment Short Test (FAST) at the end of the treatment respect to basal. | Hetero-administered | 6 weeks | 
| Global assessment of Functioning (GAF) at the end of the treatment respect to basal. | Hetero-administered | 6 weeks | 
| Response to treatment | 50% reduction in HDRS-17 | 2 and 6 weeks | 
| Response to treatment | 50% reduction in MADRS | 2 and 6 weeks | 
| Remission | HDRS-17<8 points | 2 and 6 weeks | 
| Remission | MADRS<11 POINTS | 2 and 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TMS, iTBS, Depression, Bipolar depression, Antidepressants, Neuroimaging, PET-MRI