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Investigating Predictors of Treatment Response in Treatment-Resistant Depression (TRD) With Interleaved TMS/fMRI

Primary Purpose

Major Depressive Disorder, Depression

Status
Completed
Phase
Not Applicable
Locations
Canada
Study Type
Interventional
Intervention
repetitive transcranial magnetic stimulation
Sponsored by
University of British Columbia
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Major Depressive Disorder focused on measuring repetitive transcranial magnetic stimulation, rTMS, neurostimulation, biomarker, treatment-resistant

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

TRD Patient Inclusion Criteria:

Patients will be included if they:

  1. are outpatients
  2. are voluntary and competent to consent to treatment
  3. have a Mini-International Neuropsychiatric Interview (MINI) confirmed diagnosis of MDD, single or recurrent
  4. are between the ages of 18 and 80 years
  5. have failed to achieve a clinical response to at least one adequate dose of an antidepressant based on an Antidepressant Treatment History Form (ATHF) score of score ≥ 3 in the current episode OR have been unable to tolerate at least 2 separate trials of antidepressants of inadequate dose and duration (ATHF 1 or 2)
  6. have a score ≥ 22 on the IDS item
  7. have had no increase or initiation of any psychotropic medication in the 4 weeks prior to initiation of rTMS
  8. able to adhere to the treatment schedule
  9. pass the TMS adult safety screening (TASS) questionnaire

First Episode Depression Inclusion Criteria:

Patients will be included if they:

  1. are outpatients
  2. are voluntary and competent to consent to treatment
  3. have a Mini-International Neuropsychiatric Interview (MINI) confirmed diagnosis of MDD, single or recurrent
  4. are between the ages of 18 and 80 years
  5. have never received and adequate antidepressant trial and are not currently taking any antidepressant.
  6. have a score ≥ 12 on the IDS item
  7. are on no psychotropic medication for the 4 weeks prior to initiation of rTMS, with the exception of lorazepam up to 2mg or equivalent dose of benzodiazepine or prescribed sleeping aids including (zopiclone up to 15mg/d, zolpidem up to 10mg/d).
  8. able to adhere to the treatment schedule
  9. pass the TMS adult safety screening (TASS) questionnaire

Patient Exclusion Criteria:

Patients are excluded if they:

  1. have a history of substance dependence or abuse within the last 3 months
  2. have a concomitant major unstable medical illness, cardiac pacemaker or implanted medication pump
  3. have active suicidal intent
  4. are pregnant
  5. have a lifetime Mini-International Neuropsychiatric Interview (MINI) diagnosis of bipolar I or II disorder, schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, or current psychotic symptoms
  6. have a MINI diagnosis of obsessive compulsive disorder, post-traumatic stress disorder (current or within the last year), anxiety disorder (generalized anxiety disorder, social anxiety disorder, panic disorder), or dysthymia, assessed by a study investigator to be primary and causing greater impairment than MDD
  7. have a diagnosis of any personality disorder, and assessed by a study investigator to be primary and causing greater impairment than MDD
  8. have failed a course of ECT in the current episode or previous episode
  9. have received rTMS for any previous indication due to the potential compromise of expectancy effects
  10. have any significant neurological disorder or insult including, but not limited to: any condition likely to be associated with increased intracranial pressure, space occupying brain lesion, any history of seizure except those therapeutically induced by ECT, cerebral aneurysm, Parkinson's disease, Huntington's chorea, multiple sclerosis, significant head trauma with loss of consciousness for greater than 5 minutes
  11. have an intracranial 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
  12. If participating in psychotherapy, must have been in stable treatment for at least 3 months prior to entry into the study, with no anticipation of change in the frequency of therapeutic sessions, or the therapeutic focus over the duration of the study
  13. have a clinically significant laboratory abnormality, in the opinion of the one of the principal investigators
  14. are currently (or in the last 4 weeks) taking lorazepam greater than 2 mg daily (or equivalent) or any dose of an anticonvulsant, due to the potential to limit rTMS efficacy
  15. have a non-correctable clinically significant sensory impairment (i.e., cannot hear well enough to cooperate with interview).
  16. have failed more than 5 adequate trials of medication in the current episode.
  17. Exclusion criteria for MRI: Those with a history of cranial, thoracic or abdominal surgery, with pacemakers, artificial joins or other metallic implants will be excluded from the MRI scan. Subjects that have agreed to participate in the MRI portion of the study will be pre- screened for any potential metal fragments in the body (particularly in the orbits) if they have had any history of doing metal work or have been involved in use/deployment of ammunitions/explosives, welding, piping etc.). In these cases a CT scan will be performed prior to the MRI scan

    ----------

Healthy Control Inclusion Criteria

Participants will be included if they:

  1. are voluntary and competent to consent to the study
  2. are between the ages of 18 and 80
  3. are fluent in English, sufficient to complete interviews and cognitive testing
  4. have no history of Axis I or Axis II disorders, as determined by the MINI
  5. pass the TMS adult safety screening (TASS) questionnaire

Healthy Control Exclusion Criteria:

Participants will be excluded if they:

  1. have a lifetime Mini-International Neuropsychiatric Interview (MINI) diagnosis of bipolar I or II disorder, schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, or current psychotic symptoms
  2. have a MINI diagnosis of obsessive compulsive disorder, post-traumatic stress disorder (current or within the last year), anxiety disorder (generalized anxiety disorder, social anxiety disorder, panic disorder), dysthymia or any personality disorder
  3. have history of bipolar disorder or psychosis in first degree relative (parents, siblings, offspring)
  4. are unable to provide family history of biological family (i.e., adopted persons are not eligible)
  5. have a history of substance dependence within the last 3 months
  6. have a concomitant major unstable medical illness
  7. have any significant neurological disorder or insult including, but not limited to: any condition likely to be associated with increased intracranial pressure, space occupying brain lesion, cerebral aneurysm, Parkinson's disease, Huntington's chorea, multiple sclerosis, significant head trauma with loss of consciousness for greater than or equal to 5 minutes
  8. have a non-correctable clinically significant sensory impairment (i.e., cannot hear well enough to cooperate with interview).
  9. have a personal or family history of seizures
  10. Exclusion criteria for MRI: Those with a history of cranial, thoracic or abdominal surgery, with pacemakers, artificial joins or other metallic implants will be excluded from the MRI scan. Those who are pregnant will also be excluded from the MRI scan. Subjects that have agreed to participate in the MRI portion of the study will be pre-screened for any potential metal fragments in the body (particularly in the orbits) if they have had any history of doing metal work or have been involved in use/deployment of ammunitions/explosives, welding, piping etc.)

Sites / Locations

  • Non-Invasive Neurostimulation Therapies lab, University of British Columbia

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

1 Hz rTMS

Arm Description

30 minutes of 1 Hz rTMS to the right dorsolateral prefrontal cortex (R_DLPFC)

Outcomes

Primary Outcome Measures

Inventory of Depressive Symptomatology (IDS-30)
The inventory of depressive symptomatology is a clinician-rated depression scale. Outcome will be total score. Minimum score is 0 and maximum score is 84. Higher scores indicate worse severity.

Secondary Outcome Measures

Quick Inventory of Depressive Symptomatology (QIDS-SR)
The quick inventory of depressive symptomatology is self-rated depression scale. Outcome will be total score. Minimum score is 0 and maximum score is 27. Higher scores indicate worse severity.

Full Information

First Posted
August 9, 2018
Last Updated
January 8, 2021
Sponsor
University of British Columbia
Collaborators
University of Victoria
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1. Study Identification

Unique Protocol Identification Number
NCT03642522
Brief Title
Investigating Predictors of Treatment Response in Treatment-Resistant Depression (TRD) With Interleaved TMS/fMRI
Official Title
Investigating Predictors of Treatment Response in Treatment-Resistant Depression (TRD) With Interleaved TMS/fMRI
Study Type
Interventional

2. Study Status

Record Verification Date
January 2021
Overall Recruitment Status
Completed
Study Start Date
November 1, 2018 (Actual)
Primary Completion Date
March 30, 2020 (Actual)
Study Completion Date
August 1, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of British Columbia
Collaborators
University of Victoria

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
The purpose of this trial is identify biomarkers of response to repetitive transcranial magnetic stimulation (rTMS) in individuals with first episode or treatment resistant depression. These biomarkers include simultaneous TMS-fMRI (functional magnetic resonance imaging), a blood smear, cognitive and behavioural assessments, questionnaires, and neurophysiology.
Detailed Description
This study is enrolling 60 individuals with treatment-resistant depression. All patients will receive four weeks of 1-Hz rTMS to the right dorsolateral prefrontal cortex (R_DLPFC). In addition, all patients will undergo baseline and post-treatment measures, including rTMS while they are in the MRI scanner, neurophysiology (Electroencephalography (EEG)/Near-Infrared Spectroscopy (NIRS)), cognitive testing, behavioural assessments and a blood smear. There will also be a 1-week, 4-week, and 12-week follow-up following completion of the treatment course.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Major Depressive Disorder, Depression
Keywords
repetitive transcranial magnetic stimulation, rTMS, neurostimulation, biomarker, treatment-resistant

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
72 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1 Hz rTMS
Arm Type
Experimental
Arm Description
30 minutes of 1 Hz rTMS to the right dorsolateral prefrontal cortex (R_DLPFC)
Intervention Type
Device
Intervention Name(s)
repetitive transcranial magnetic stimulation
Other Intervention Name(s)
rTMS
Intervention Description
rTMS is a Health-Canada- and FDA-approved treatment for treatment-resistant depression (TRD), using focused magnetic field pulses to stimulate brain regions involved in emotion regulation, safely and non-invasively. rTMS can be applied at varying discharge frequencies which have differential effects on cortical excitability. At a low frequency (≤ 1Hz), rTMS reduces cortical excitability, while at frequencies greater than 1 Hz, rTMS facilitates cortical excitability3. In MDD, either high- frequency rTMS (HF-rTMS) applied over the left dorsolateral prefrontal cortex (DLPFC) or low- frequency rTMS (LF-rTMS) applied over the right DLPFC have similar efficacy. This study utilizes low frequency rTMS to the right DLPFC.
Primary Outcome Measure Information:
Title
Inventory of Depressive Symptomatology (IDS-30)
Description
The inventory of depressive symptomatology is a clinician-rated depression scale. Outcome will be total score. Minimum score is 0 and maximum score is 84. Higher scores indicate worse severity.
Time Frame
4 weeks
Secondary Outcome Measure Information:
Title
Quick Inventory of Depressive Symptomatology (QIDS-SR)
Description
The quick inventory of depressive symptomatology is self-rated depression scale. Outcome will be total score. Minimum score is 0 and maximum score is 27. Higher scores indicate worse severity.
Time Frame
4 weeks
Other Pre-specified Outcome Measures:
Title
Quick Inventory of Depressive Symptomatology (QIDS-SR)
Description
The quick inventory of depressive symptomatology is self-rated depression scale. Outcome will be total score. Minimum score is 0 and maximum score is 27. Higher scores indicate worse severity.
Time Frame
16 weeks
Title
Inventory of Depressive Symptomatology (IDS-30)
Description
The quick inventory of depressive symptomatology is self-rated depression scale. Outcome will be total score. Minimum score is 0 and maximum score is 27. Higher scores indicate worse severity.
Time Frame
16 weeks
Title
The Montgomery-Åsberg Depression Rating Scale (MADRS)
Description
The Montgomery-Åsberg Depression Rating Scale is a clinician-rated depression scale. Outcome will be total score. Minimum score is 0 and maximum score is 60. Higher scores indicate worse severity.
Time Frame
4 weeks
Title
The Montgomery-Åsberg Depression Rating Scale (MADRS)
Description
The Montgomery-Åsberg Depression Rating Scale is a clinician-rated depression scale. Outcome will be total score. Minimum score is 0 and maximum score is 60. Higher scores indicate worse severity.
Time Frame
16 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
TRD Patient Inclusion Criteria: Patients will be included if they: are outpatients are voluntary and competent to consent to treatment have a Mini-International Neuropsychiatric Interview (MINI) confirmed diagnosis of MDD, single or recurrent are between the ages of 18 and 80 years have failed to achieve a clinical response to at least one adequate dose of an antidepressant based on an Antidepressant Treatment History Form (ATHF) score of score ≥ 3 in the current episode OR have been unable to tolerate at least 2 separate trials of antidepressants of inadequate dose and duration (ATHF 1 or 2) have a score ≥ 22 on the IDS item have had no increase or initiation of any psychotropic medication in the 4 weeks prior to initiation of rTMS able to adhere to the treatment schedule pass the TMS adult safety screening (TASS) questionnaire First Episode Depression Inclusion Criteria: Patients will be included if they: are outpatients are voluntary and competent to consent to treatment have a Mini-International Neuropsychiatric Interview (MINI) confirmed diagnosis of MDD, single or recurrent are between the ages of 18 and 80 years have never received and adequate antidepressant trial and are not currently taking any antidepressant. have a score ≥ 12 on the IDS item are on no psychotropic medication for the 4 weeks prior to initiation of rTMS, with the exception of lorazepam up to 2mg or equivalent dose of benzodiazepine or prescribed sleeping aids including (zopiclone up to 15mg/d, zolpidem up to 10mg/d). able to adhere to the treatment schedule pass the TMS adult safety screening (TASS) questionnaire Patient Exclusion Criteria: Patients are excluded if they: have a history of substance dependence or abuse within the last 3 months have a concomitant major unstable medical illness, cardiac pacemaker or implanted medication pump have active suicidal intent are pregnant have a lifetime Mini-International Neuropsychiatric Interview (MINI) diagnosis of bipolar I or II disorder, schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, or current psychotic symptoms have a MINI diagnosis of obsessive compulsive disorder, post-traumatic stress disorder (current or within the last year), anxiety disorder (generalized anxiety disorder, social anxiety disorder, panic disorder), or dysthymia, assessed by a study investigator to be primary and causing greater impairment than MDD have a diagnosis of any personality disorder, and assessed by a study investigator to be primary and causing greater impairment than MDD have failed a course of ECT in the current episode or previous episode have received rTMS for any previous indication due to the potential compromise of expectancy effects have any significant neurological disorder or insult including, but not limited to: any condition likely to be associated with increased intracranial pressure, space occupying brain lesion, any history of seizure except those therapeutically induced by ECT, cerebral aneurysm, Parkinson's disease, Huntington's chorea, multiple sclerosis, significant head trauma with loss of consciousness for greater than 5 minutes have an intracranial 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 If participating in psychotherapy, must have been in stable treatment for at least 3 months prior to entry into the study, with no anticipation of change in the frequency of therapeutic sessions, or the therapeutic focus over the duration of the study have a clinically significant laboratory abnormality, in the opinion of the one of the principal investigators are currently (or in the last 4 weeks) taking lorazepam greater than 2 mg daily (or equivalent) or any dose of an anticonvulsant, due to the potential to limit rTMS efficacy have a non-correctable clinically significant sensory impairment (i.e., cannot hear well enough to cooperate with interview). have failed more than 5 adequate trials of medication in the current episode. Exclusion criteria for MRI: Those with a history of cranial, thoracic or abdominal surgery, with pacemakers, artificial joins or other metallic implants will be excluded from the MRI scan. Subjects that have agreed to participate in the MRI portion of the study will be pre- screened for any potential metal fragments in the body (particularly in the orbits) if they have had any history of doing metal work or have been involved in use/deployment of ammunitions/explosives, welding, piping etc.). In these cases a CT scan will be performed prior to the MRI scan ---------- Healthy Control Inclusion Criteria Participants will be included if they: are voluntary and competent to consent to the study are between the ages of 18 and 80 are fluent in English, sufficient to complete interviews and cognitive testing have no history of Axis I or Axis II disorders, as determined by the MINI pass the TMS adult safety screening (TASS) questionnaire Healthy Control Exclusion Criteria: Participants will be excluded if they: have a lifetime Mini-International Neuropsychiatric Interview (MINI) diagnosis of bipolar I or II disorder, schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, or current psychotic symptoms have a MINI diagnosis of obsessive compulsive disorder, post-traumatic stress disorder (current or within the last year), anxiety disorder (generalized anxiety disorder, social anxiety disorder, panic disorder), dysthymia or any personality disorder have history of bipolar disorder or psychosis in first degree relative (parents, siblings, offspring) are unable to provide family history of biological family (i.e., adopted persons are not eligible) have a history of substance dependence within the last 3 months have a concomitant major unstable medical illness have any significant neurological disorder or insult including, but not limited to: any condition likely to be associated with increased intracranial pressure, space occupying brain lesion, cerebral aneurysm, Parkinson's disease, Huntington's chorea, multiple sclerosis, significant head trauma with loss of consciousness for greater than or equal to 5 minutes have a non-correctable clinically significant sensory impairment (i.e., cannot hear well enough to cooperate with interview). have a personal or family history of seizures Exclusion criteria for MRI: Those with a history of cranial, thoracic or abdominal surgery, with pacemakers, artificial joins or other metallic implants will be excluded from the MRI scan. Those who are pregnant will also be excluded from the MRI scan. Subjects that have agreed to participate in the MRI portion of the study will be pre-screened for any potential metal fragments in the body (particularly in the orbits) if they have had any history of doing metal work or have been involved in use/deployment of ammunitions/explosives, welding, piping etc.)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Fidel Vila-Rodriguez, MD
Organizational Affiliation
University of British Columbia
Official's Role
Principal Investigator
Facility Information:
Facility Name
Non-Invasive Neurostimulation Therapies lab, University of British Columbia
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V6T2A1
Country
Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
35582784
Citation
Ge R, Humaira A, Gregory E, Alamian G, MacMillan EL, Barlow L, Todd R, Nestor S, Frangou S, Vila-Rodriguez F. Predictive Value of Acute Neuroplastic Response to rTMS in Treatment Outcome in Depression: A Concurrent TMS-fMRI Trial. Am J Psychiatry. 2022 Jul;179(7):500-508. doi: 10.1176/appi.ajp.21050541. Epub 2022 May 18.
Results Reference
derived

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Investigating Predictors of Treatment Response in Treatment-Resistant Depression (TRD) With Interleaved TMS/fMRI

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