Bipolar Depression
Conditions
Keywords
Bipolar disorder, Depression, intermittent Theta-Burst Stimulation (rTMS), neuromodulatory technique
Brief summary
Bipolar Disorder is a common condition that is characterized by periods of mood elevation however periods of chronic and recurring depressive episodes are more common and can be severely disabling. Effective treatments exist, however a significant portion of bipolar depressed patients do not respond to, or have difficulty tolerating many of these interventions. Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive neuromodulatory technique that is effective in major depression and there is evidence for its efficacy in bipolar depression which needs to be assessed in larger randomized controlled trials. This study is a randomised, double-blind, sham-controlled trial over four weeks. The primary objective is to assess improvement in depressive symptoms in acute bipolar depressed patients on treatment with intermittent Theta-Burst Stimulation (iTBS) in comparison to sham-rTMS.
Detailed description
rTMS is a treatment that involves stimulating a certain area of the brain with magnetic field pulses. Over time, the magnetic field pulses can gradually change the activity level of the stimulated brain region and help symptoms of bipolar depression. The device used in this study has been approved by Health Canada for therapeutic use since 2002. Participants will complete a screen visit to determine eligibility based on the inclusion/exclusion criteria. If the participants are not eligible, no further study procedures will be conducted. Eligible subjects will be randomized to receive either active iTBS-rTMS or sham rTMS treatment (scalp stimulation with no magnetic pulse) daily for four weeks (20 sessions) to the left dorsolateral prefrontal cortex (DLPFC). All participants will complete a MRI (to target the left DLPFC region of the brain and functional activity), EEG & fNIRS, lab work, and neurocognitive testing prior to the commencement and post rTMS treatment. Efficacy, safety and tolerability will be evaluated at screen visit, during daily rTMS treatments, clinic visits and post rTMS treatment. All participants will have a phone interview two weeks post rTMS treatment.
Interventions
rTMS is a non-invasive procedure in which cerebral electrical activity is influenced by a rapidly changing magnetic field. The magnetic field is created by a plastic-encased coil which is placed over the patient's scalp. The magnetic field can be directed onto specific areas of the brain. rTMS can modulate cerebral activity by low or high frequencies. Over time, the magnetic field pulses can gradually change the activity level of the stimulated brain region and help symptoms of bipolar depression.
DEVICESham rTMS
Sham rTMS involves a click replicating the sound of the magnetic discharge, without any magnetic pulse being delivered.
Sponsors
University of British Columbia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Are a male or female aged 18 to 70 years. * Have a diagnosis of Bipolar Disorder with a current ongoing episode of depression. * Are not currently experiencing a mania. * Have failed to achieve a clinical response or have been unable to tolerate an adequate dose of at least one of the medications used for treating Bipolar depression * Are taking an anti-manic agent (lithium or valproate) or an atypical antipsychotic (quetiapine, lurasidone, aripiprazole, ziprasidone, risperidone, olanzapine), or a combination of the above, or a combination of any of them with lamotrigine 100-400 mg daily. Lamotrigine alone for bipolar II disorder is permitted. * current medications have been at a stable dose in the 2 weeks prior to randomization * Are capable of understanding, consenting to, and complying with the requirements of the study
Exclusion criteria
* Have an alcohol or substance abuse or dependence within the last 3 months. * Are at a significant risk of harm to themselves or others * Are pregnant or planning on becoming pregnant in near future or lactating. * Have a personal or family history of seizures. * Have a history of unstable or inadequately treated medical illnesses, including moderate to severe brain injury or head trauma. * Have a primary diagnosis of other psychiatric disorders (other than Bipolar) or personality disorders that are of primary concern and causing greater impairment other than bipolar disorder. * are currently taking more than 3 of the antipsychotics. * Have failed a course of ECT in the current episode. * History of non-response to rTMS treatment. * If participating in psychotherapy, you must have been in stable treatment for at least 3 months prior to entry into the study, * Currently (or in the last 4 weeks) taking more than 2 mg daily (or equivalent) of lorazepam or any dose of medication for seizures * Have a pacemaker, or an implant (e.g., aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) or any other metal object within or near the head, excluding the mouth that cannot be safely removed. * Have a non-correctable clinically significant sensory impairment (i.e., cannot hear well enough to cooperate with interview).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Montgomery Asberg Depression Rating Scale (MADRS) Scale Score | Baseline, Week 2, Week 4 | The primary outcome was the change in score on the Montgomery-Asberg Depression Rating Scale from baseline to study end. A higher score means a worse outcome. Min value is 0, Max value is 60 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Meeting Criteria for Clinical Remission | Baseline to Week 4 (assessed at Week 2 and Week 4, Week 4 reported) | Clinical Remission is defined as a MADRS score ≤12 |
| Overall Well Being | Baseline to 4 weeks | The visual analog scale (VAS) is a self report measure that captures the over all well being. Min 0-worse health to Max 100- best health. |
| Brief Illness Perception Questionnaire | Baseline to 4 weeks | Brief Illness Perception Questionnaire measures participant's perception of illness. Min = 0 Max = 80. Higher score means worse outcome. |
| Number of Participants With Clinical Response | Baseline to Week 4 (assessed at Week 2 and Week 4, Week 4 reported) | Response rates are defined as patients showing ≥50% reduction in MADRS scores. |
| Quality of Life Questionnaire | Baseline to 4 weeks | The Quality of Life in Bipolar Disorder scale is a 56 item scale which assesses 12 core and 2 optional (work and study) domains, each containing four self-report items (1: strongly disagree to 5: strongly agree). An overall score (range: 48-240) may be calculated by summing responses to the 48 items of the core 12 domains. Higher scores reflect greater satisfaction with a person's quality of life. |
| Patient Global Impression Rating Scale: Severity | Baseline to 4 weeks | Patient Global Impression Rating Scale: Severity rates how depressed the participant is at the current time. 1-4 (1 is normal and 4 is severe) |
| Patient Global Impression Rating Scale- Improvement | Week 4 | Rates current depression compared to baseline. Min =1 Max =7 Higher scores mean worse outcome. |
| Sheehan Disability Scale (SDS) | Baseline to 4 weeks | The Sheehan Disability Scale is a five-item, self-rated questionnaire designed to measure the extent to which a patient's disability due to an illness interferes with work/school, social life/leisure activities, and family life/home responsibilities. Each subscale score (a work disability, a social life disability, a family life disability) is combined into a single total score (sum of the non missing responses for items 1-3) representing a global impairment rating, ranging from 0 to 30, with higher scores indicative of significant functional impairment. |
Countries
Canada
Participant flow
Recruitment details
Participants were recruited by referral, as well as online and community advertisements 2 Canadian centers (University of British Columbia \[UBC\], British Columbia, Canada; and University of Calgary \[UC\], Alberta, Canada) between October 2016 and March 2020 .
Pre-assignment details
Of the 71 assessed for eligibility 37 were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Active iTBS rTMS The active arm involves magnetic stimulation of the brain to the left dorsolateral prefrontal cortex (DLPFC) daily for four weeks. The active arm will be receiving intermittent Theta-Burst (iTBS) repetitive Transcranial Magnetic Stimulation (rTMS) to deliver magnetic pulses.
iTBS repetitive Transcranial Magnetic Stimulation (rTMS): rTMS is a non-invasive procedure in which cerebral electrical activity is influenced by a rapidly changing magnetic field. The magnetic field is created by a plastic-encased coil which is placed over the patient's scalp. The magnetic field can be directed onto specific areas of the brain. rTMS can modulate cerebral activity by low or high frequencies. Over time, the magnetic field pulses can gradually change the activity level of the stimulated brain region and help symptoms of bipolar depression. | 18 |
| Sham rTMS sham rTMS treatment involves scalp stimulation with no magnetic pulse daily for four weeks (20 sessions). Sham rTMS involves only the click replicating the sound of the magnetic discharge, without any magnetic pulse being delivered.
Sham rTMS: Sham rTMS involves a click replicating the sound of the magnetic discharge, without any magnetic pulse being delivered. | 19 |
| Total | 37 |
Baseline characteristics
| Characteristic | Total | Active iTBS rTMS | Sham rTMS |
|---|---|---|---|
| Age, Continuous | 43.86 years STANDARD_DEVIATION 13.87 | 44.78 years STANDARD_DEVIATION 13.71 | 43.00 years STANDARD_DEVIATION 14.34 |
| Primary Diagnosis Bipolar disorder type I | 21 Participants | 11 Participants | 10 Participants |
| Primary Diagnosis Bipolar disorder type II | 16 Participants | 7 Participants | 9 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 35 Participants | 17 Participants | 18 Participants |
| Sex: Female, Male Female | 23 Participants | 11 Participants | 12 Participants |
| Sex: Female, Male Male | 14 Participants | 7 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 19 |
| other Total, other adverse events | 7 / 7 | 9 / 9 |
| serious Total, serious adverse events | 0 / 18 | 0 / 19 |
Outcome results
Primary
Montgomery Asberg Depression Rating Scale (MADRS) Scale Score
The primary outcome was the change in score on the Montgomery-Asberg Depression Rating Scale from baseline to study end. A higher score means a worse outcome. Min value is 0, Max value is 60
Time frame: Baseline, Week 2, Week 4
Population: Diagnosis of BD type I or type II by Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria, experiencing a major depressive episode (MDE).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active iTBS rTMS | Montgomery Asberg Depression Rating Scale (MADRS) Scale Score | Baseline | 32.27 score on a scale | Standard Deviation 4.04 |
| Active iTBS rTMS | Montgomery Asberg Depression Rating Scale (MADRS) Scale Score | Week 2 | 24.12 score on a scale | Standard Deviation 10.09 |
| Active iTBS rTMS | Montgomery Asberg Depression Rating Scale (MADRS) Scale Score | Week 4 | 24.46 score on a scale | Standard Deviation 10.82 |
| Sham rTMS | Montgomery Asberg Depression Rating Scale (MADRS) Scale Score | Baseline | 31.52 score on a scale | Standard Deviation 5.22 |
| Sham rTMS | Montgomery Asberg Depression Rating Scale (MADRS) Scale Score | Week 2 | 25.17 score on a scale | Standard Deviation 8.24 |
| Sham rTMS | Montgomery Asberg Depression Rating Scale (MADRS) Scale Score | Week 4 | 23.06 score on a scale | Standard Deviation 10.58 |
Secondary
Brief Illness Perception Questionnaire
Brief Illness Perception Questionnaire measures participant's perception of illness. Min = 0 Max = 80. Higher score means worse outcome.
Time frame: Baseline to 4 weeks
Population: Not all participants completed the questionnaire.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active iTBS rTMS | Brief Illness Perception Questionnaire | Baseline | 60.35 score on a scale | Standard Deviation 4.67 |
| Active iTBS rTMS | Brief Illness Perception Questionnaire | Week 4 | 57.31 score on a scale | Standard Deviation 8.27 |
| Sham rTMS | Brief Illness Perception Questionnaire | Baseline | 59.13 score on a scale | Standard Deviation 8.21 |
| Sham rTMS | Brief Illness Perception Questionnaire | Week 4 | 58.93 score on a scale | Standard Deviation 8.37 |
Secondary
Number of Participants Meeting Criteria for Clinical Remission
Clinical Remission is defined as a MADRS score ≤12
Time frame: Baseline to Week 4 (assessed at Week 2 and Week 4, Week 4 reported)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active iTBS rTMS | Number of Participants Meeting Criteria for Clinical Remission | 3 Participants |
| Sham rTMS | Number of Participants Meeting Criteria for Clinical Remission | 3 Participants |
Secondary
Number of Participants With Clinical Response
Response rates are defined as patients showing ≥50% reduction in MADRS scores.
Time frame: Baseline to Week 4 (assessed at Week 2 and Week 4, Week 4 reported)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active iTBS rTMS | Number of Participants With Clinical Response | 3 Participants |
| Sham rTMS | Number of Participants With Clinical Response | 3 Participants |
Secondary
Overall Well Being
The visual analog scale (VAS) is a self report measure that captures the over all well being. Min 0-worse health to Max 100- best health.
Time frame: Baseline to 4 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active iTBS rTMS | Overall Well Being | Baseline | 41.83 score on a scale | Standard Deviation 18.29 |
| Active iTBS rTMS | Overall Well Being | Week 4 | 58.13 score on a scale | Standard Deviation 17.13 |
| Sham rTMS | Overall Well Being | Week 4 | 46.66 score on a scale | Standard Deviation 18.09 |
| Sham rTMS | Overall Well Being | Baseline | 35.21 score on a scale | Standard Deviation 18.8 |
Secondary
Patient Global Impression Rating Scale- Improvement
Rates current depression compared to baseline. Min =1 Max =7 Higher scores mean worse outcome.
Time frame: Week 4
Population: Not all participants completed the scale.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active iTBS rTMS | Patient Global Impression Rating Scale- Improvement | 3.53 score on a scale | Standard Deviation 1.24 |
| Sham rTMS | Patient Global Impression Rating Scale- Improvement | 3.20 score on a scale | Standard Deviation 1.26 |
Secondary
Patient Global Impression Rating Scale: Severity
Patient Global Impression Rating Scale: Severity rates how depressed the participant is at the current time. 1-4 (1 is normal and 4 is severe)
Time frame: Baseline to 4 weeks
Population: Not all participants completed the scale at Week 4.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active iTBS rTMS | Patient Global Impression Rating Scale: Severity | Baseline | 3.16 score on a scale | Standard Deviation 0.51 |
| Active iTBS rTMS | Patient Global Impression Rating Scale: Severity | Week 4 | 2.60 score on a scale | Standard Deviation 0.82 |
| Sham rTMS | Patient Global Impression Rating Scale: Severity | Baseline | 3.05 score on a scale | Standard Deviation 0.8 |
| Sham rTMS | Patient Global Impression Rating Scale: Severity | Week 4 | 2.66 score on a scale | Standard Deviation 0.81 |
Secondary
Quality of Life Questionnaire
The Quality of Life in Bipolar Disorder scale is a 56 item scale which assesses 12 core and 2 optional (work and study) domains, each containing four self-report items (1: strongly disagree to 5: strongly agree). An overall score (range: 48-240) may be calculated by summing responses to the 48 items of the core 12 domains. Higher scores reflect greater satisfaction with a person's quality of life.
Time frame: Baseline to 4 weeks
Population: Not all participants completed the questionnaire.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active iTBS rTMS | Quality of Life Questionnaire | Baseline | 109 score on a scale | Standard Deviation 18.67 |
| Active iTBS rTMS | Quality of Life Questionnaire | Week 4 | 136.18 score on a scale | Standard Deviation 33.81 |
| Sham rTMS | Quality of Life Questionnaire | Baseline | 108.78 score on a scale | Standard Deviation 26.34 |
| Sham rTMS | Quality of Life Questionnaire | Week 4 | 130.76 score on a scale | Standard Deviation 36.54 |
Secondary
Sheehan Disability Scale (SDS)
The Sheehan Disability Scale is a five-item, self-rated questionnaire designed to measure the extent to which a patient's disability due to an illness interferes with work/school, social life/leisure activities, and family life/home responsibilities. Each subscale score (a work disability, a social life disability, a family life disability) is combined into a single total score (sum of the non missing responses for items 1-3) representing a global impairment rating, ranging from 0 to 30, with higher scores indicative of significant functional impairment.
Time frame: Baseline to 4 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active iTBS rTMS | Sheehan Disability Scale (SDS) | Baseline | 23.83 score on a scale | Standard Deviation 5.09 |
| Active iTBS rTMS | Sheehan Disability Scale (SDS) | Week 4 | 19.40 score on a scale | Standard Deviation 10.32 |
| Sham rTMS | Sheehan Disability Scale (SDS) | Baseline | 23.44 score on a scale | Standard Deviation 6.43 |
| Sham rTMS | Sheehan Disability Scale (SDS) | Week 4 | 19.23 score on a scale | Standard Deviation 8.26 |