Efficacy and Biomarkers of Response of TBS in Treatment Resistant Depression (EMTtfNI)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Bipolar Depression; Resistant Depression, Treatment
• Intervention / Treatment: Device: Theta Burst Transcranial Magnetic Bilateral Stimulation; Device: Theta Burst Transcranial Magnetic Unilateral Stimulation; Device: Theta Burst Transcranial Magnetic Sham Stimulation

Detailed Description

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)

• Study Type: Interventional
• Enrollment (Estimated): 96
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yolanda Cañada, MD; Phone Number: +34961244154; Email: canyada_yol@gva.es

Study Locations

• Spain
  • Valencia, Spain, 46026
    • Recruiting
    • Hospital Universitario y Politecnico La Fe
    • Contact: Yolanda Cañada, MD; Phone Number: +961244154; Email: canyada_yol@gva.es

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group Bilateral; 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; TMS protocol of 22 sessions of bilateral active 1800 pulses.
Active Comparator: Group Unilateral; 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; TMS protocol of 22 sessions of left active 1800 pulses and right sham 1800 pulses.
Placebo Comparator: Group Placebo; 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; TMS protocol of 22 sessions of sham bilateral 1800 pulses.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Instituto de Investigacion Sanitaria La Fe
• Collaborators: Instituto de Salud Carlos III; Hospital Universitario La Fe; Spanish Agency of Medicines and Health Products
• Investigators: Principal Investigator: Pilar Sierra San Miguel, PhD, Instituto de Investigación Sanitaria La Fe

Publications and helpful links

General Publications

• Blumberger DM, Vila-Rodriguez F, Thorpe KE, Feffer K, Noda Y, Giacobbe P, Knyahnytska Y, Kennedy SH, Lam RW, Daskalakis ZJ, Downar J. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Lancet. 2018 Apr 28;391(10131):1683-1692. doi: 10.1016/S0140-6736(18)30295-2. Epub 2018 Apr 26. Erratum In: Lancet. 2018 Jun 23;391(10139):e24.
• Li CT, Chen MH, Juan CH, Huang HH, Chen LF, Hsieh JC, Tu PC, Bai YM, Tsai SJ, Lee YC, Su TP. Efficacy of prefrontal theta-burst stimulation in refractory depression: a randomized sham-controlled study. Brain. 2014 Jul;137(Pt 7):2088-98. doi: 10.1093/brain/awu109. Epub 2014 May 10.
• Fitzgerald PB, Chen L, Richardson K, Daskalakis ZJ, Hoy KE. A pilot investigation of an intensive theta burst stimulation protocol for patients with treatment resistant depression. Brain Stimul. 2020 Jan-Feb;13(1):137-144. doi: 10.1016/j.brs.2019.08.013. Epub 2019 Aug 22.

Study record dates

Study Major Dates

• Study Start (Actual): September 15, 2021
• Primary Completion (Estimated): February 1, 2025
• Study Completion (Estimated): February 28, 2025

Study Registration Dates

• First Submitted: August 2, 2021
• First Submitted That Met QC Criteria: August 2, 2021
• First Posted (Actual): August 10, 2021

Study Record Updates

• Last Update Posted (Estimated): February 22, 2024
• Last Update Submitted That Met QC Criteria: February 21, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Depression; Neuroimaging; TMS; Bipolar depression; Antidepressants; iTBS; PET-MRI
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Bipolar and Related Disorders; Depression; Depressive Disorder; Bipolar Disorder; Depressive Disorder, Treatment-Resistant
• Other Study ID Numbers: 2021-326-1; PI 2022-280-1 (Other Grant/Funding Number: Carlos III Health Institute); 21-0040 (Other Identifier: AEMPS, NEOPS code)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No