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Biomarker-guided rTMS for Treatment Resistant Depression (BioTMS)

Primary Purpose

Treatment Resistant Depression, Major Depressive Disorder

Status

Recruiting

Phase

Phase 3

Locations

United States

Study Type

Interventional

Intervention

Repetitive Transcranial Magnetic Stimulation

About this trial

This is an interventional treatment trial for Treatment Resistant Depression

Eligibility Criteria

22 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Age 22 to 65 years
Major Depressive Disorder (by M.I.N.I., Diagnostic Statistical Manual V (DSM-V criteria); Verification by evaluation by licensed study psychiatrist or psychologist
At least moderately severe depression (17-item Hamilton Depression Rating Scale greater than or equal to 18)
Failure to respond in the current episode to at least 1 antidepressant medication at an adequate dose and duration as measured by a modified Antidepressant Treatment History Form
Off antidepressants OR on a stable dose of antidepressants for greater than or equal to four weeks with plans to remain on this stable dose during the study
Any and all medication intended to treat depression or reduce symptoms of depression must be discontinued or maintained at the same daily dose for ≥ 4 weeks prior to enrollment and for the duration of the study
Capacity to consent
Written consent to allow communication between members of the research team and the patient's outpatient clinician(s) (psychiatrist, psychotherapist, nurse practitioner, primary care physician, or equivalent) as needed to ensure safety
Ability to safely participate in MRI
Fluent in English

Exclusion Criteria:

Imminent risk of suicide (based on the Columbia-Suicide Severity Rating Scale)
Current depressive episode greater than or equal to 2 years duration
Presence of primary psychiatric diagnoses other than MDD and/or comorbid generalized anxiety disorder (GAD) or phobia (e.g., post-traumatic stress disorder; obsessive-compulsive disorder; MDD w psychotic features; primary psychotic illness; Bipolar I or II)
Evidence of cognitive impairment (MMSE score falling greater than or equal to 1 SD below the mean score for his or her age and education)
Have met criteria for any significant substance use disorder within the past six months
Recent onset (within 8 weeks of screening) psychotherapy, including, but not limited to: any form of treatment, aid, or therapy that has intensively and extensively examined the patient's psychological history, including, but not limited to: cognitive behavioral therapy, dialectical behavioral therapy, interpersonal therapy, and family-focused therapy
Prior exposure to any form of TMS during the current depressive episode.
Participated in any clinical trial with an investigational drug or device within the past 6 weeks prior to screening
History of neurosurgery to treat a neurological or psychiatric disorder
Evidence or history of significant neurological disorder, including moderate-severe head trauma, stroke, Parkinson's disease or other movement disorder (except benign essential tremor), epilepsy, history of seizures, cerebrovascular disease, dementia, increased intracranial pressure, history of repetitive or severe head trauma, or primary or secondary tumors within the central nervous system
Implanted electronic devices and/or conductive objects in or near the head, including metal plates, aneurysm coils, cochlear implants, ocular implants, deep brain stimulation devices and stents
Any implanted device that is activated or controlled in any way by physiological signals, including, but not limited to: deep brain stimulators, cochlear implants, and vagus nerve stimulators
Patients with major depressive disorder who have failed to receive clinical benefit from Vagus Nerve Stimulation (VNS) or are currently receiving these therapies.
History of seizures (except juvenile febrile seizures) or any condition/concurrent medication that could notably lower seizure threshold
Individuals who are pregnant, nursing, contemplating pregnancy within the length of the study or, in the opinion of the investigator, not adherent to a medically acceptable method of birth control
History or presence of any disease, medical condition or physical condition that, in the opinion of the investigator, may compromise, interfere, limit, effect, or reduce the participant's ability to complete a treatment study lasting up to 21 weeks
Abnormal bloodwork for electrolytes, thyroid and liver function
Individuals who are taking > 300 mg daily dose of bupropion in any formulation (immediate, extended, or slow-release)
Individuals who are taking tricyclic antidepressants.

Sites / Locations

Stanford UniversityRecruiting
Weill Cornell MedicineRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Experimental

Active Comparator

Arm Label

Standard of Care

Targeted Side Arm

Opposite Side Arm

Arm Description

FDA-cleared, standard-of-care iTBS repetitive Transcranial Magnetic Stimulation targeting the left dorsolateral prefrontal cortex (DLPFC), regardless of the depression subtype (biotype) determined by a magnetic resonance imaging (MRI) scan.

iTBS rTMS targeting the area of the brain (DLPFC or dorsomedial prefrontal cortex DMPFC)) that we hypothesize will be most effective for that subject's biotype (confirmation arm).

iTBS rTMS targeting the opposite site (DLPFC or DMPFC) than the one we hypothesize will be most effective for that subject's biotype (disconfirmation arm).

Outcomes

Primary Outcome Measures

Change in depression, as measured by the Hamilton Depression Rating Scale (HAMD17)

The Hamilton Depression Rating Scale (HAMD17) is a 17 item clinician-rated measure of depression severity. Scores of 0-7 = Normal, 8-13 = Mild Depression, 14-18 = Moderate Depression, 19-22 = Severe Depression, ≥ 23 = Very Severe Depression

Secondary Outcome Measures

Change in depression, as measured by the Quick Inventory of Depressive Symptomology (QIDS)

The Quick Inventory of Depressive Symptomology (QIDS) is a 16 item self-report measure of depression severity. Scores range from 0 to 27, with higher scores indicating greater severity of depression.

Change in Resting State fMRI Connectivity

Calculated from Functional Magnetic Resonance Imaging (fMRI) scan conducted while participant is awake but not completing any tasks in the scanner. Used to determine biotype of depression for treatment assignment and to determine if any changes in resting state connectivity have taken place post-TMS treatment.

Full Information

NCT ID

NCT04041479

First Posted

July 31, 2019

Last Updated

May 8, 2023

Sponsor

Weill Medical College of Cornell University

Collaborators

National Institute of Mental Health (NIMH), Stanford University

1. Study Identification

Unique Protocol Identification Number

NCT04041479

Brief Title

Biomarker-guided rTMS for Treatment Resistant Depression

Acronym

BioTMS

Official Title

Efficacy of Biomarker-guided rTMS for Treatment Resistant Depression

Study Type

Interventional

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Recruiting

Study Start Date

September 1, 2021 (Actual)

Primary Completion Date

April 2026 (Anticipated)

Study Completion Date

August 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Weill Medical College of Cornell University

Collaborators

National Institute of Mental Health (NIMH), Stanford University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Yes

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Repetitive transcranial magnetic stimulation (rTMS) is a treatment for depression. The investigators are continuing to learn how to optimize outcomes from rTMS treatment. The purpose of this research project is to use brain network connectivity patterns as measured by resting state functional magnetic resonance imaging (fMRI) to confirm a way to optimize the use of rTMS to treat depression. In addition, the study aims to gain a better understanding of how rTMS influences brain networks.

Detailed Description

Major depressive disorder (MDD) is a leading cause of global disability, and approximately 30% of MDD patients are resistant to antidepressant pharmacotherapy. Repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC) is an FDA-cleared intervention with proven efficacy in treatment-resistant depression, but only 30-40% of these patients achieve remission after a single course. Other studies have shown that rTMS targeting the dorsomedial prefrontal cortex (DMPFC) is comparably effective, but biomarkers for informing target site selection do not exist. Diagnostic heterogeneity has been an obstacle to biomarker discovery efforts. Recently, we developed and validated an approach to diagnose four novel MDD subtypes or "biotypes' defined by resting state functional connectivity (RSFC) patterns and predicting differing antidepressant responses at the individual level to rTMS. This pivotal trial will test a novel, biotype-guided treatment selection strategy motivated by the hypothesis that an individual patient's likelihood of responding to left DLFPC vs.DMPFC rTMS is determined in part by individual differences in 1) the degree to which their symptoms are driven by dysfunction in specific cerebral network targets comprising Valence Systems; and 2) the degree to which dysfunction in those targets can be modulated by stimulating the left DLPFC or DMPFC. Subjects (N=348; 174 from this site) will be randomized to receive a) biotype-guided rTMS targeting the DMPFC or left DLPFC; b) to a disconfirmation arm receiving rTMS targeting the opposite site; and c) to a third arm receiving FDA-cleared, standard-of-care rTMS targeting the left DLFPC, regardless of biotype. The dosage and method of delivery of rTMS for all arms are as follows: intermittent theta burst stimulation (iTBS) will be delivered at 120% of the resting motor threshold. It will be administered in triplet 50 Hz bursts, repeated at 5 Hz with a duty cycle of 2 s on and 8 s off, for a total of 600 pulses per session and a total duration of 3 min 9 s. All patients will be assessed before and after treatment on a battery of fMRI, behavioral, and clinical assessments. The primary goal is to confirm the efficacy of a novel RSFC biomarker-guided approach to differential treatment selection in treatment resistant depression.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Treatment Resistant Depression, Major Depressive Disorder

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Model Description

Human subjects in the proposed protocol will be randomized to receive a) biotype-guided rTMS to the left DLPFC or to the DMPFC; b) rTMS targeted to the opposite site; and c) standard-of-care left DLPFC rTMS. The dosage and method of delivery of rTMS are as follows: intermittent theta burst stimulation (iTBS) will be delivered at 120% of the resting motor threshold. It will be administered in triplet 50 Hz bursts, repeated at 5 Hz with a duty cycle of 2 s on and 8 s off, for a total of 600 pulses per session and a total duration of 3 min 9 s. Participants will receive screening and diagnostic interviews, phenotypic assessment (including demographic information, cognitive assessments, and behavioral functioning), structured clinical interviews, and magnetic resonance imaging (including structural and functional MRI).

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

348 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Standard of Care

Arm Type

Active Comparator

Arm Description

Arm Title

Targeted Side Arm

Arm Type

Experimental

Arm Description

iTBS rTMS targeting the area of the brain (DLPFC or dorsomedial prefrontal cortex DMPFC)) that we hypothesize will be most effective for that subject's biotype (confirmation arm).

Arm Title

Opposite Side Arm

Arm Type

Active Comparator

Arm Description

iTBS rTMS targeting the opposite site (DLPFC or DMPFC) than the one we hypothesize will be most effective for that subject's biotype (disconfirmation arm).

Intervention Type

Device

Intervention Name(s)

Repetitive Transcranial Magnetic Stimulation

Intervention Description

iTBS rTMS targeting the DMPFC or left DLPFC

Intervention Type

Device

Intervention Name(s)

Repetitive Transcranial Magnetic Stimulation

Intervention Description

iTBS rTMS targeting the left DLPFC

Primary Outcome Measure Information:

Title

Change in depression, as measured by the Hamilton Depression Rating Scale (HAMD17)

Description

Time Frame

Baseline and 1 Week Post Treatment (8-10 weeks)

Secondary Outcome Measure Information:

Title

Change in depression, as measured by the Quick Inventory of Depressive Symptomology (QIDS)

Description

The Quick Inventory of Depressive Symptomology (QIDS) is a 16 item self-report measure of depression severity. Scores range from 0 to 27, with higher scores indicating greater severity of depression.

Time Frame

Baseline and Post Treatment (7-9 weeks)

Title

Change in Resting State fMRI Connectivity

Description

Time Frame

Baseline and after completion of treatment (7-9 weeks)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

22 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Age 22 to 65 years Major Depressive Disorder (by M.I.N.I., Diagnostic Statistical Manual V (DSM-V criteria)); Verification by evaluation by licensed study psychiatrist or psychologist At least moderately severe depression (17-item Hamilton Depression Rating Scale greater than or equal to 18) Failure to respond in the current episode to at least 1 antidepressant medication at an adequate dose and duration as measured by a modified Antidepressant Treatment History Form. The Maudsley Staging Method will also be used to quantify treatment resistance. Any and all medication intended to treat depression or reduce symptoms of depression must be discontinued or maintained at the same daily dose for ≥ 4 weeks prior to enrollment and for the duration of the study Capacity to consent Written consent to allow communication between members of the research team and the patient's outpatient clinician(s) (psychiatrist, psychotherapist, nurse practitioner, primary care physician, or equivalent) as needed to ensure safety Ability to safely participate in MRI Fluent in English Exclusion Criteria: Imminent risk of suicide (based on the Columbia-Suicide Severity Rating Scale) Current depressive episode greater than or equal to 2 years duration Presence of primary psychiatric diagnoses other than MDD and/or comorbid generalized anxiety disorder (GAD) or phobia (e.g., post-traumatic stress disorder; obsessive-compulsive disorder; MDD w psychotic features; primary psychotic illness; Bipolar I or II) DSM-5 defined addiction to, dependence on, abuse of, or misuse of any substance during the prior 12 months, excluding nicotine Evidence of cognitive impairment (MMSE score falling greater than or equal to 1 SD below the mean score for his or her age and education) Recent onset (within 8 weeks of screening) psychotherapy, including, but not limited to: any form of treatment, aid, or therapy that has intensively and extensively examined the patient's psychological history, including, but not limited to: cognitive behavioral therapy, dialectical behavioral therapy, interpersonal therapy, and family-focused therapy Prior exposure to an adequate dose and duration of the TMS treatment protocol administered in this study during the current depressive episode. Participated in any clinical trial with an investigational drug or device within the past 6 weeks prior to screening History of neurosurgery to treat a neurological or psychiatric disorder Evidence or history of significant neurological disorder, including moderate-severe head trauma, stroke, Parkinson's disease or other movement disorder (except benign essential tremor), epilepsy, history of seizures, cerebrovascular disease, dementia, increased intracranial pressure, history of repetitive or severe head trauma, or primary or secondary tumors within the central nervous system Implanted electronic devices and/or conductive objects in or near the head, including metal plates, aneurysm coils, cochlear implants, ocular implants, deep brain stimulation devices and stents Any implanted device that is activated or controlled in any way by physiological signals, including, but not limited to: deep brain stimulators, cochlear implants, and vagus nerve stimulators Patients with major depressive disorder who have failed to receive clinical benefit from Vagus Nerve Stimulation (VNS) or are currently receiving these therapies. History of seizures (except juvenile febrile seizures) or any condition/concurrent medication that could notably lower seizure threshold Individuals who are pregnant, nursing, contemplating pregnancy within the length of the study or, in the opinion of the investigator, not adherent to a medically acceptable method of birth control History or presence of any disease, medical condition or physical condition that, in the opinion of the investigator, may compromise, interfere, limit, effect, or reduce the participant's ability to complete a treatment study lasting up to 21 weeks Abnormal bloodwork for electrolytes, thyroid and liver function Individuals who are taking > 300 mg daily dose of bupropion in any formulation (immediate, extended, or slow-release) Individuals who are taking tricyclic antidepressants.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Megan Johnson

Phone

646-962-2900

tmsinfo@med.cornell.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Lindsay Victoria, PhD

liv3002@med.cornell.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Conor Liston, MD, PhD

Organizational Affiliation

Weill Medical College of Cornell University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Stanford University

City

Stanford

State/Province

California

ZIP/Postal Code

94305

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Derrick Buchanan, PhD

dmbuchan@stanford.edu

Facility Name

Weill Cornell Medicine

City

New York

State/Province

New York

ZIP/Postal Code

10065

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Conor Liston, MD, PhD

Phone

646-962-6293

col2004@med.cornell.edu

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

In accordance with NIH policy we will share our data via the National Database for Clinical Trials related to Mental Illness (NDCT). NDCT is a secure data platform that will allow us to share research data and tools from our analysis of resting-state fMRI data, task-based fMRI data, and fMRI-guided rTMS data. Specifically, data to be shared will include de-identified neuroimaging scans and rTMS targeting data, in addition to phenotypic data such as demographics, diagnosis, treatment history, and anonymized, item-level responses to clinical and cognitive assessments. These data will then be made available through the NDCT, and NIH-funded repository that ensures that data are secure and shared in accord with applicable NIH regulations.

IPD Sharing Time Frame

Raw data (e.g., MRI data and assessment responses) will be deposited on the NDCT every six months (January 15 and June 15 of each year of the award period), in accordance with NIH policy for use of the NDCT in clinical trials research. Curated data will be uploaded annually beginning in the third year of the project.

IPD Sharing Access Criteria

The data may be shared with researchers at institutions with a Federal Wide Assurance, who will be able to gain access to NDCT data by submitting a data access request, in line with NDCT policies.

Learn more about this trial

Biomarker-guided rTMS for Treatment Resistant Depression

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