Evaluation of Theta-burst Stimulation Efficacy, Safety and Tolerability in Major Depressive Episodes of Bipolar I Disorder

Evaluation of Theta-burst Stimulation Efficacy, Safety and Tolerability in Major Depressive Episodes of Bipolar I Disorder: Randomized, Controlled, Double-blind, Parallel-group Clinical Trial

INTRODUCTION: Pharmacological treatment of major depressive episodes in bipolar disorder (BD) is characterized by suboptimal efficacy rates, poor tolerability and adherence, delayed onset of action, and iatrogenic mood swings. The use of repetitive transcranial magnetic stimulation (rTMS) has been presented as an effective, safe and well-tolerated alternative to the treatment of uni- and bipolar depressive episodes. Recently, a new rTMS protocol was introduced, theta-burst stimulation (TBS), whose studies have shown similar efficacy with a shorter time interval than conventional rTMS. Most clinical trials performed to date evaluate the use of TBS in patients with unipolar depression or mixed samples of uni and bipolar patients. The effectiveness of TBS exclusively in BD has not been properly studied. METHODS: We will perform a 6-week, double-blind, randomized, parallel-group, sham-controlled clinical trial of active or sham TBS. We will recruit 60 patients aged between 18 and 65 years with a diagnosis of BD type I in a current moderate or severe major depressive episode resistant to at least two first- or second-line pharmacological treatments, according to CANMAT guidelines. The primary outcome measure will be the assessment of TBS efficacy through difference in scores on 17-item Hamilton Depression Scale (HAM-D) from baseline until the end of week 6 of intervention between active and sham groups. KEYWORDS: randomized clinical trial; transcranial magnetic stimulation; bipolar affective disorder; major depression.

Study Overview

• Status: Active, not recruiting
• Conditions: Bipolar Disorder, Type 1
• Intervention / Treatment: Device: Active Theta Burst Stimulation (TBS); Device: Sham Theta Burst Stimulation (TBS)

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Brazil
  • Sao Paulo, Brazil, 05403-010
    • Institute of Psychiatry, University of Sao Paulo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Current moderate or severe major depressive episode in bipolar I disorder assessed with Hamilton Depression Rating Scale (HAM-D) score ≥ 17 points.
• Any appropriate first or second line pharmacological regimen in accordance with Canmat guidelines to treat a major depressive episode in bipolar I disorder:

Quetiapine 300 - 600 mg/dia; Lithium serum levels 0,6 - 1,2 meq/L; Lamotrigine 100 - 200 mg/dia; Lurasidone 20 - 120 mg/dia; Divalproex; Lithium/Divalproex + Lurasidone; Lithium/Divalproex + Lamotrigine; Olanzapine 5 - 20 mg/day + Fluoxetine 20 - 60 mg/day; Lithium/Divalproex + SSRI/Bupropion.

Exclusion Criteria:

• Concomitant diagnosis of other neuropsychiatric disorders such as: schizophrenia, dementias, mental retardation, organic mental disorder, or epilepsy;
• Acute suicide ideation (assessed by interview and clinical evaluation);
• Acute psychotic depression (assessed by interview and clinical evaluation);
• Suspected or confirmed pregnancy;
• Women in breastfeeding;
• Severe or unstable clinical disease;
• Previous rTMS treatment;
• Specific contraindications to TBS: previous epileptic seizures; change in electroencephalogram at some point in life; previous stroke; previous severe traumatic brain injury (with neurosurgery); metallic object on head (except mouth) as projectile piece, surgical clip, welding fragments; any implanted device (cardiac pacemaker, intravenous catheter).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active TBS arm; Patients randomized to this arm will receive active TBS 5 consecutive days of the week (Monday to Friday) in the first 3 weeks and then 2 alternate days of the week (with interval of at least 1 day between sessions) for another 3 weeks comprising 21 sections.	Device: Active Theta Burst Stimulation (TBS); Each session will be comprised of ACTIVE TBS: intermittent excitatory stimulation (iTBS) in the left dorsolateral prefrontal cortex totaling 37,800 pulses.
Sham Comparator: Sham TBS arm; Patients randomized to this arm will receive sham TBS 5 consecutive days of the week (Monday to Friday) in the first 3 weeks and then 2 alternate days of the week (with interval of at least 1 day between sessions) for another 3 weeks comprising 21 sections.	Device: Sham Theta Burst Stimulation (TBS); Each session will be comprised of SHAM TBS: intermittent excitatory stimulation (iTBS) in the left dorsolateral prefrontal cortex totaling 37,800 pulses.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary Outcome Measure	Change in Hamilton Depression Rating Scale (HAM-D)	From baseline to week 6

Collaborators and Investigators

• Sponsor: University of Sao Paulo

Study record dates

Study Major Dates

• Study Start (Actual): July 10, 2022
• Primary Completion (Anticipated): August 1, 2024
• Study Completion (Anticipated): August 1, 2024

Study Registration Dates

• First Submitted: August 11, 2022
• First Submitted That Met QC Criteria: August 12, 2022
• First Posted (Actual): August 15, 2022

Study Record Updates

• Last Update Posted (Actual): August 15, 2022
• Last Update Submitted That Met QC Criteria: August 12, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: randomized clinical trial; transcranial magnetic stimulation; major depression; bipolar affective disorder
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Bipolar and Related Disorders; Disease; Bipolar Disorder
• Other Study ID Numbers: StudyTBS

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: No
• product manufactured in and exported from the U.S.: No