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Continuous Theta Burst Stimulation as an add-on Treatment for Bipolar Depression

Primary Purpose

Bipolar Disorder, Bipolar Depression, Bipolar I Disorder

Status
Unknown status
Phase
Not Applicable
Locations
Belgium
Study Type
Interventional
Intervention
cTBS
Sham cTBS
Sponsored by
Universiteit Antwerpen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Bipolar Disorder focused on measuring bipolar depression, TMS, transcranial magnetic stimulation, add-on treatment

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Diagnostic and Statistical Manual-IV defined bipolar subjects (bipolar types I and II), depressed or mixed phase, confirmed by the Mini-International Neuropsychiatric Interview (MINI-plus 5.0.0.)
  • Hamilton Rating Scale for Depression-17 score of 17 or more.
  • Stable psychotropic medication regimen for at least 2 weeks prior to randomization and patient is willing to remain on a stable regimen from screening (S) after the second measurement point T2 (2 to 3 weeks).

Antidepressants:

  • On stable antidepressant treatment for 4 weeks.
  • Stable antidepressant medication but dose has been recently changed (higher/lower dose): duration of 2 weeks should lie between change of medication dose and screening (S).
  • If the patient recently stopped the antidepressant treatment, a wash-out period of 14 days is necessary.

Mood stabilizers:

  • On a stable dose of mood-stabilizing medication (e.g., lithium, valproate, carbamazepine, lamotrigine, antipsychotic agents) for at least 4 weeks. In case of change in dose of the mood stabilizing medication, participants can be included given that no or minimal improvement is seen after 2 weeks of dosing.
  • Atypical antipsychotics
  • On a stable dose of for at least 4 weeks. In case of change in dose of antipsychotics, participants can be included given that no or minimal improvement is seen after 2 weeks of dosing.
  • Benzodiazepines are permitted to a maximum allowed dose of equivalent of 40 mg diazepam. If the dosage has been recently changed: stable dose during 2 weeks.
  • Able to read, understand and sign the Informed Consent Form.

Exclusion Criteria:

  • Contra-indications for TMS treatment:

    • Current or past history of epilepsy.
    • The risk of seizure with any reasons.
    • Organic brain damage (for example mass brain lesions, cerebrovascular accident, …).
    • Neurosurgical interventions.
    • Having a pacemaker or metal or magnetic objects in the brain.
  • Unipolar depression
  • Psychotic disorder (MINI-plus 5.0.0; DSM-IV codes 295.10, 295.20, .30, .40, .60, .70, .90, 297.10, 298.90); exceptions are: depression with psychotic features MINI-Plus 5.0.0; DSM code 296.23)
  • Current alcohol dependence (MINI-plus 5.0.0. DSM IV code 303.9) (in the last year)
  • Current substance abuse or dependence (DSM-IV codes 304.00-.90, 305.20 -.70) (in the last year), with the exception of nicotine and caffeine (DSM IV codes 305.10 and 305.90)
  • Suicide attempt within 6 months before the start of the study
  • Pregnancy or lactation

Sites / Locations

  • University Hospital of Brussels
  • University Psychiatric Hospital DuffelRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Sham Comparator

Arm Label

Active cTBS

Sham cTBS

Arm Description

Outcomes

Primary Outcome Measures

Changes in depression severity clinician-rated
Hamilton rating scale for depression (HRSD-17); total scores ranging from 0 to 52. A higher score is indicative of greater depressive pathology

Secondary Outcome Measures

Changes in depression severity self-report
Beck Depression Inventory (BDI-II); total scores ranging from 0 to 63. Higher total scores indicate more severe depressive symptoms.
Changes in suicidal thoughts - clinician-rated
Columbia-suicide severity rating scale (total score ranges from 0 to 25; a higher score represent a higher intensity of suicidality)
Changes in cognitive symptoms (1)
Continuous performance test (CPT), a measure of a person's sustained and selective attention: d-prime (the quotient of hits/false alarms that indicate the response sensitivity for discrimination of target from nontarget stimuli). Greater scores represent better ability to distinguish and detect X and non-X stimuli (better sustained attention)
Changes in cognitive symptoms (2)
Symbol Digit Substitution Test (SDST), examining processing speed. Differentiating between the cognitive and the psychomotor processes of slowing (matching time and writing time; msec)
Changes in cognitive symptoms (3)
Stroop test; examining response inhibition (Stroop response interference score)
Changes in psychomotor symptoms (1)
CORE assessment of psychomotor functioning; total score ranging from 0 to 54. A higher score is indicative of psychomotor impairment (a score of 21 or more is indicative of melancholic depression)
Changes in psychomotor symptoms (2)
Accelometer tool (MotionWatch 8®, CamNtech, Cambridge, UK; measuring gross motor performance): total day activity level (counts per hour). Lower values indicate reduction in gross motor activity. *Cut-off levels from a control group are being collected in another research project of this research group.
Changes in psychomotor symptoms (3)
Line-copying task (LCT): initiation and movement time (msec)
Change in biological markers (1)
Plasma levels of C reactive protein (CRP)
Change in biological markers (2)
Cytokines (pg/ml)
Change in biological markers (3)
Kynurenines tryptophan catabolites (TRYCAT) levels (mmol/l)
Change in biological markers (4)
Brain-derived neurotrophic factor (BDNF; ng/ml)
Differences in adverse events following cTBS or sham - self report
Adverse effects questionnaire
Differences in development of (hypo)manic symptoms
Young mania rating scale (YMRS): evaluates the presence and severity of mania. The score ranges from 0 to 60. Scores higher than 12 are indicative for mania, scores of 2 or lower indicate euthymia.

Full Information

First Posted
June 5, 2018
Last Updated
April 24, 2019
Sponsor
Universiteit Antwerpen
Collaborators
Universitair Ziekenhuis Brussel
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1. Study Identification

Unique Protocol Identification Number
NCT03603561
Brief Title
Continuous Theta Burst Stimulation as an add-on Treatment for Bipolar Depression
Official Title
Continuous Theta Burst Transcranial Magnetic Stimulation as an add-on Treatment for Bipolar Depression: a Multicenter Randomized Sham-controlled Trial
Study Type
Interventional

2. Study Status

Record Verification Date
April 2019
Overall Recruitment Status
Unknown status
Study Start Date
August 1, 2018 (Actual)
Primary Completion Date
July 2020 (Anticipated)
Study Completion Date
July 2020 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Universiteit Antwerpen
Collaborators
Universitair Ziekenhuis Brussel

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This study aims to investigate the clinical efficacy of continuous theta burst stimulation (cTBS) on the right DLPFC as an add-on treatment in bipolar depression. The study consists of three phases. Phase 1: Bipolar depressed patients will be selected by a certified psychiatrist, who will administer (semi-)structured clinical interviews (M.I.N.I.-Plus 5.0.0, HRSD-17). The presence of exclusion criteria will be evaluated. Eligible patients will undergo MRI brain imaging for TMS neuronavigation Phase 2: Baseline clinical, cognitive and psychomotor assessments will take place. Patients will also undergo blood samples for laboratory and research assessments. TBS involves applying triple-pulse 50 Hz bursts given at a rate of 5 Hz uninterrupted trains (1). Patients will be treated with in total 20 continuous Theta Burst Stimulation (cTBS) session (900 pulses per session) over the right dorsolateral prefrontal cortex, which will be spread over 4 days. A stimulation intensity of 100% of the subject's resting motor threshold (rMT) of the right abductor pollicis brevis muscle will used. Patients will be randomized to receive either the real cTBS or sham treatment. Sham stimulation will be applied with a sham coil. The sham coil produces identical sounds but is not associated with a stimulus sensation compared to the coil delivering real stimulation cTBS. The investigators expect that real cTBS treatment and not sham will result in a significant and clinical meaningful response. Phase 3: Two post-treatment assessment moments will take place respectively 3 (max. 4) days and 10 (max. 11) days after the last treatment day. The assessments are the same clinical, cognitive and psychomotor assessments as in phase 2.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bipolar Disorder, Bipolar Depression, Bipolar I Disorder, Bipolar II Disorder, Depression, Mood Disorders, Mental Disorder
Keywords
bipolar depression, TMS, transcranial magnetic stimulation, add-on treatment

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderOutcomes Assessor
Allocation
Randomized
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Active cTBS
Arm Type
Active Comparator
Arm Title
Sham cTBS
Arm Type
Sham Comparator
Intervention Type
Device
Intervention Name(s)
cTBS
Intervention Description
In the cTBS arm, the patients will receive 5 daily session cTBS (5 times uninterrupted train of 900 pulses) separated by a 15 min interval. Patients will be treated with in total 20 cTBS sessions over the right dorsolateral prefrontal cortex, spread over 4 days. A stimulation intensity of 100 % of the resting motor threshold (rMT) of the right abductor pollicis brevis muscle will be used.
Intervention Type
Device
Intervention Name(s)
Sham cTBS
Intervention Description
The sham coil has been specifically developed to mimic the real one but is not associated with a stimulus sensation compared to the coil delivering real stimulation cTBS.
Primary Outcome Measure Information:
Title
Changes in depression severity clinician-rated
Description
Hamilton rating scale for depression (HRSD-17); total scores ranging from 0 to 52. A higher score is indicative of greater depressive pathology
Time Frame
Screening, baseline, 3 days after cTBS or sham (+/- day 7), 10 days after cTBS or sham (+/- day 14)
Secondary Outcome Measure Information:
Title
Changes in depression severity self-report
Description
Beck Depression Inventory (BDI-II); total scores ranging from 0 to 63. Higher total scores indicate more severe depressive symptoms.
Time Frame
Baseline, 3 days after cTBS or sham (+/- day 7), 10 days after cTBS or sham (+/- day 14)
Title
Changes in suicidal thoughts - clinician-rated
Description
Columbia-suicide severity rating scale (total score ranges from 0 to 25; a higher score represent a higher intensity of suicidality)
Time Frame
Baseline, 3 days after cTBS or sham (+/- day 7), 10 days after cTBS or sham (+/- day 14)
Title
Changes in cognitive symptoms (1)
Description
Continuous performance test (CPT), a measure of a person's sustained and selective attention: d-prime (the quotient of hits/false alarms that indicate the response sensitivity for discrimination of target from nontarget stimuli). Greater scores represent better ability to distinguish and detect X and non-X stimuli (better sustained attention)
Time Frame
Baseline, 3 days after cTBS or sham (+/- day 7), 10 days after cTBS or sham (+/- day 14)
Title
Changes in cognitive symptoms (2)
Description
Symbol Digit Substitution Test (SDST), examining processing speed. Differentiating between the cognitive and the psychomotor processes of slowing (matching time and writing time; msec)
Time Frame
Baseline, 3 days after cTBS or sham (+/- day 7), 10 days after cTBS or sham (+/- day 14)
Title
Changes in cognitive symptoms (3)
Description
Stroop test; examining response inhibition (Stroop response interference score)
Time Frame
Baseline, 3 days after cTBS or sham (+/- day 7), 10 days after cTBS or sham (+/- day 14)
Title
Changes in psychomotor symptoms (1)
Description
CORE assessment of psychomotor functioning; total score ranging from 0 to 54. A higher score is indicative of psychomotor impairment (a score of 21 or more is indicative of melancholic depression)
Time Frame
Baseline, 3 days after cTBS or sham (+/- day 7), 10 days after cTBS or sham (+/- day 14)
Title
Changes in psychomotor symptoms (2)
Description
Accelometer tool (MotionWatch 8®, CamNtech, Cambridge, UK; measuring gross motor performance): total day activity level (counts per hour). Lower values indicate reduction in gross motor activity. *Cut-off levels from a control group are being collected in another research project of this research group.
Time Frame
Baseline, 3 days after cTBS or sham (+/- day 7), 10 days after cTBS or sham (+/- day 14)
Title
Changes in psychomotor symptoms (3)
Description
Line-copying task (LCT): initiation and movement time (msec)
Time Frame
Baseline, 3 days after cTBS or sham (+/- day 7), 10 days after cTBS or sham (+/- day 14)
Title
Change in biological markers (1)
Description
Plasma levels of C reactive protein (CRP)
Time Frame
Baseline and 10 days after cTBS or sham (+/- day 14)
Title
Change in biological markers (2)
Description
Cytokines (pg/ml)
Time Frame
Baseline and 10 days after cTBS or sham (+/- day 14)
Title
Change in biological markers (3)
Description
Kynurenines tryptophan catabolites (TRYCAT) levels (mmol/l)
Time Frame
Baseline and 10 days after cTBS or sham (+/- day 14)
Title
Change in biological markers (4)
Description
Brain-derived neurotrophic factor (BDNF; ng/ml)
Time Frame
Baseline and 10 days after cTBS or sham (+/- day 14)
Title
Differences in adverse events following cTBS or sham - self report
Description
Adverse effects questionnaire
Time Frame
3 days after cTBS or sham (+/- day 7)
Title
Differences in development of (hypo)manic symptoms
Description
Young mania rating scale (YMRS): evaluates the presence and severity of mania. The score ranges from 0 to 60. Scores higher than 12 are indicative for mania, scores of 2 or lower indicate euthymia.
Time Frame
Baseline, 3 days after cTBS or sham (+/- day 7), 10 days after cTBS or sham (+/- day 14)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnostic and Statistical Manual-IV defined bipolar subjects (bipolar types I and II), depressed or mixed phase, confirmed by the Mini-International Neuropsychiatric Interview (MINI-plus 5.0.0.) Hamilton Rating Scale for Depression-17 score of 17 or more. Stable psychotropic medication regimen for at least 2 weeks prior to randomization and patient is willing to remain on a stable regimen from screening (S) after the second measurement point T2 (2 to 3 weeks). Antidepressants: On stable antidepressant treatment for 4 weeks. Stable antidepressant medication but dose has been recently changed (higher/lower dose): duration of 2 weeks should lie between change of medication dose and screening (S). If the patient recently stopped the antidepressant treatment, a wash-out period of 14 days is necessary. Mood stabilizers: On a stable dose of mood-stabilizing medication (e.g., lithium, valproate, carbamazepine, lamotrigine, antipsychotic agents) for at least 4 weeks. In case of change in dose of the mood stabilizing medication, participants can be included given that no or minimal improvement is seen after 2 weeks of dosing. Atypical antipsychotics On a stable dose of for at least 4 weeks. In case of change in dose of antipsychotics, participants can be included given that no or minimal improvement is seen after 2 weeks of dosing. Benzodiazepines are permitted to a maximum allowed dose of equivalent of 40 mg diazepam. If the dosage has been recently changed: stable dose during 2 weeks. Able to read, understand and sign the Informed Consent Form. Exclusion Criteria: Contra-indications for TMS treatment: Current or past history of epilepsy. The risk of seizure with any reasons. Organic brain damage (for example mass brain lesions, cerebrovascular accident, …). Neurosurgical interventions. Having a pacemaker or metal or magnetic objects in the brain. Unipolar depression Psychotic disorder (MINI-plus 5.0.0; DSM-IV codes 295.10, 295.20, .30, .40, .60, .70, .90, 297.10, 298.90); exceptions are: depression with psychotic features MINI-Plus 5.0.0; DSM code 296.23) Current alcohol dependence (MINI-plus 5.0.0. DSM IV code 303.9) (in the last year) Current substance abuse or dependence (DSM-IV codes 304.00-.90, 305.20 -.70) (in the last year), with the exception of nicotine and caffeine (DSM IV codes 305.10 and 305.90) Suicide attempt within 6 months before the start of the study Pregnancy or lactation
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Kaat Hebbrecht, Dr
Phone
15304048
Ext
+32
Email
kaat.hebbrecht@emmaus.be
First Name & Middle Initial & Last Name or Official Title & Degree
Bernard Sabbe, PhD
Phone
15304034
Ext
+32
Email
bernard.sabbe@ua.ac.be
Facility Information:
Facility Name
University Hospital of Brussels
City
Brussels
ZIP/Postal Code
1000
Country
Belgium
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Chris Baeken, PhD
Phone
9 332 43 94
Ext
+32
Email
chris.baeken@uzbrussel.be
First Name & Middle Initial & Last Name & Degree
Dieter Zeeuws, MD
Phone
2 477 60 12
Ext
+32
Email
dieter.zeeuws@uzbrussel.be
Facility Name
University Psychiatric Hospital Duffel
City
Duffel
ZIP/Postal Code
2570
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kaat Hebbrecht, Dr
Phone
15304048
Ext
+32
Email
kaat.hebbrecht@emmaus.be
First Name & Middle Initial & Last Name & Degree
Bernard Sabbe, PhD
Phone
15304034
Ext
+32
Email
bernard.sabbe@ua.ac.be

12. IPD Sharing Statement

Citations:
PubMed Identifier
15664172
Citation
Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron. 2005 Jan 20;45(2):201-6. doi: 10.1016/j.neuron.2004.12.033.
Results Reference
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Continuous Theta Burst Stimulation as an add-on Treatment for Bipolar Depression

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