An Open Label Trial of TMS Therapy for Bipolar Depression

• Sponsor: Sheppard Pratt Health System (Other)
• Overall Status: Completed
• CT.gov ID: NCT02640950
• Collaborator: Mayo Clinic (Other)
• Enrollment: 31
• Locations: 2
• Arm: 1
• Duration (Months): 55
• Patients Per Site: 15.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

Transcranial Magnetic Stimulation (TMS) is an increasingly accepted neurostimulation- based treatment for major depressive disorder. While there is a growing anecdotal database supporting its use in bipolar depression the investigators propose to collect open label efficacy and safety data in a small population of patients with clinically verified bipolar disorder.

Condition or Disease	Intervention/Treatment	Phase
Bipolar Depression	Device: NeuroStar TMS	N/A

Detailed Description

The investigators propose to screen patients with bipolar depression I or II, who are already on acceptable mood stabilization. They may or may not be on antidepressants at the time of screening but subjects on antidepressants would be taken off them before completing the screening phase. Those patients who have a depression of at least moderate severity without significant symptoms of activation or mania will be started on a course of open label TMS treatment of up to 35 sessions. Safety and efficacy assessments will be done weekly. Patients will complete a course of treatment when they meet remission criteria (MADRS score < 10) or at the end of 30 treatments, whichever comes first. Patient who are still judged to be improving between treatment 25 and treatment 30 will be eligible to complete up to five addition treatments as the discretion of each site's principal investigator. Patients who meet response criteria (MADRS score decreases by at least 50%) will complete the full course of 30 to 35 TMS sessions. Patients will be withdrawn for safety concerns, particularly the onset of activation suggestive of mania or a mixed state.

Patients who meet response or remission criteria will be followed monthly for up to six months to evaluate the durability of response. They will be on standard mood stabilizing medications and psychotherapy per their clinician's discretion.

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label Trial of TMS Therapy for Bipolar Depression
• Study Start Date: Dec 1, 2015
• Actual Primary Completion Date: Jul 1, 2020
• Actual Study Completion Date: Jul 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Open-Label TMS Active Transcranial Magnetic Stimulation	Device: NeuroStar TMS; Transcranial Magnetic Stimulation; Other Names: Transcranial Magnetic Stimulation

Outcome Measures

Primary Outcome Measures

1. The Percentage of Patients Who Respond or Remit After 30 to 35 Treatments Based Off of the Montgomery-Åsberg Depression Rating Scale (MADRS) [Up to 7 weeks]

   The MADRS is a clinician rated scale measuring depression severity, consisting of 10 items, each scored from 0 (normal) to 6 (severe), for a total possible score of 60; higher scores denote greater severity. A decrease in MADRS score of at lease 50% will be considered a response to treatment. A MADRS score of less than 10 will be considered remission.

2. The Percentage of Patients Who Meet Criteria for Onset of Manic Symptoms Based on the Young Mania Rating Scale (YMRS). [Up to 7 weeks]

   The Young Mania Rating Scale (YMRS) is used to determine the severity of a patient's mania. The score for the YMRS ranges form 0 to 60. Scores of 13-19 indicate minimal manic symptoms, 20-25 is mild mania, 26-37 is moderate mania, and 38-60 is severe mania. A YMRS score of 14 or greater will be used for criteria of onset of manic symptoms. The patients will be separated based on their diagnostic category of either Bipolar I Disorder or Bipolar II Disorder.

Secondary Outcome Measures

1. Hamilton Depression Rating Scale (HAM-D) to Calculate Percentage of Patients Meeting Response Criteria [Up to 7 weeks]

   The Hamilton Depression (HAM-D) Rating Scale is a scale used to measure one's depression. The scoring from the scale ranges 0 to 53. Higher scores indicate that a person is more depressed. The scoring ranges from 0-7 is normal, 8-13 is mild depression, 14-18 is moderate depression, 19-22 severe depression, and greater than or equal to 23 is very severe depression. The HAM-D response criteria will be based off a HAM-D score drop of at least 50%. Remission HAM-D score will be 7 or less.

2. Clinical Global Impression (CGI) to Calculate Percentage of Patients Meeting Response Criteria [Up to 7 weeks and 6 Month Follow Up]

   The Clinical Global Impression (CGI) Scale is used to determine the severity of a patient's depression. The scoring for the scale ranges from 1 to 7, where 1 indicates that the patient is normal and 7 indicates a severe depression. Remission criteria for the CGI score will be a 2 or less. Responders and remitters will also be followed for six months after the final treatment to see the durability of response. Percentage of patients' meeting relapse criteria will be calculated.

3. Hamilton Depression Rating Scale (HAM-D) to Average Number of Treatments Needed to Meet Remission [7 Weeks]

   For the patients meeting remission criteria (Total Number = 21) , we will calculate the number of treatments required to achieve remission. Patients who only meet response criteria will be treated for 30 to 35 sessions.

4. Clinical Global Impression (CGI) to Calculate Average Number of Treatments Needed to Meet Remission [7 Weeks]

   For the patients meeting remission criteria (Total Number = 27) , we will calculate the number of treatments required to achieve remission. Patients who only meet response criteria will be treated for 30 to 35 sessions.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria- Phase II:

1. Must be at least 18 years old.

2. Must meet DSM-5 criteria for bipolar (either I or II) depression by clinical interview and M.I.N.I. The duration of the current depressive episode must be at least 4 weeks and no longer than 3 years in length.

3. Should have a MADRS score of at least 20 at screening, an YMRS score of less than 12 and a CGI score of at least 4.

4. Must have signed the informed consent document and have a level of understanding sufficient to provide informed consent and to communicate with the investigator and site personnel.

5. Must be on a mood stabilizer acceptable to the study physician which is consistent with their diagnosis. The mood stabilizer must be at a stable dose for at least four days before starting TMS treatment.

6. If female of childbearing potential, patients must

7. have a negative urine pregnancy test at screening, and

8. not be nursing or planning a pregnancy, and

9. be on a medically acceptable method of birth control acceptable to the principal investigator.

Choices of contraception that meet the study requirements are

• Intrauterine device

• Hormonal contraception (estrogen-containing birth control pills, Vaginal ring, patch, injections or implants)

• Latex condom with spermicide

• Diaphragm with spermicide

• Cervical cap with spermicide

Females of childbearing potential who are abstinent can enroll in the study.

Exclusion Criteria- Phase II:

1. May not be directly affiliated with Sheppard Pratt Clinical Research Programs or be immediate family of Research Programs personnel.

2. Must not have another primary Axis I diagnosis.

3. The subject must not have stopped an antidepressant less than two weeks before starting TMS treatment or unable to discontinue antidepressant therapy.

4. Should have no previous history of psychosis or substance dependence or abuse within the six months prior to Screening

5. Presence of an Axis II disorder felt by the investigator to potentially interfere with study compliance would exclude a potential participant.

6. Should not have prior intolerance of TMS or significant lack of response to adequate trials of TMS.

7. Should not have a lifetime history of lack of response to ECT or VNS.

8. Should not have any medical condition likely to interfere with safe study participation.

9. Women of child-bearing potential who are not using a medically accepted means of contraception when engaging in sexual intercourse are excluded, as well as women who are pregnant or breast-feeding.

10. Positive urine screen for any substance of abuse will exclude a patient, with the exception of benzodiazepines. A satisfactory explanation in the opinion of the investigator along with a negative repeat screen prior to Visit 2 is possibly acceptable.

11. Current suicide risk, as evidenced:

12. It is the judgment of the investigator that the patient may be at risk for suicide

13. The patient has rated a "yes" to question 4 or question 5 on the Screening C-SSRS

14. The patient has attempted suicide within the past 12 months prior to Screening.

15. History of head injury, epilepsy or seizure disorder, non-removable metallic implants or objects in or around the head.

Inclusion Criteria- Phase III Patients who meet MADRS criteria for response or remission will enter Phase III, the six month follow-up phase of the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sheppard Pratt Health System	Baltimore	Maryland	United States	21204
2	Department of Psychiatry and Psychology, Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Sheppard Pratt Health System
• Mayo Clinic

Investigators

• Principal Investigator: Scott T Aaronson, MD, Sheppard Pratt Health System

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 17, 2017

More Information

Publications

None provided.

• Responsible Party: Scott T. Aaronson, M.D, Director, Clinical Research Programs, Sheppard Pratt Health System
• ClinicalTrials.gov Identifier: NCT02640950
• Other Study ID Numbers: 794736-5
• First Posted: Dec 29, 2015
• Last Update Posted: Jun 1, 2022
• Last Verified: May 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Depression; Depressive Disorder; Bipolar Disorder

Study Results

Participant Flow

Arm/Group Title	Patients With Bipolar (I or II) Depression
Arm/Group Description	Adults with bipolar (I or II) depression, per DSM-5 criteria, were recruited at Sheppard Pratt and Mayo Clinic between December 2015-February 2020 for TMS. Standardized treatment protocols employed 6 weeks of 10 Hz TMS to the left dorsolateral prefrontal cortex at 120% of motor threshold with 3,000 pulses per session in 4 second trains with intertrain intervals of 26 seconds. All patients were treated concurrently with a mood stabilizer. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale (MADRS). Response and remission were defined as MADRS score reductions of ≥ 50% or score ≤10, respectively. We examined response, remission, and potential contributing factors with multivariate and logistic regression models.
Period Title: Overall Study
STARTED	31
COMPLETED	29
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Patients With Bipolar (I or II) Depression
Arm/Group Description	Adults with bipolar (I or II) depression, per DSM-5 criteria, were recruited at Sheppard Pratt and Mayo Clinic between December 2015-February 2020 for TMS. Standardized treatment protocols employed 6 weeks of 10 Hz TMS to the left dorsolateral prefrontal cortex at 120% of motor threshold with 3,000 pulses per session in 4 second trains with intertrain intervals of 26 seconds. All patients were treated concurrently with a mood stabilizer. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale (MADRS). Response and remission were defined as MADRS score reductions of ≥ 50% or score ≤10, respectively. We examined response, remission, and potential contributing factors with multivariate and logistic regression models.
Overall Participants	31
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	30 96.8%
>=65 years	1 3.2%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.2 (14.3)
Sex: Female, Male (Count of Participants)
Female	18 58.1%
Male	13 41.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	31 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 3.2%
White	29 93.5%
More than one race	1 3.2%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	31 100%
Montgomery-Åsberg Depression Rating Scale (Number of participants) [Number]
Participants in remission at baseline	0 0%
Participants responding at baseline	0 0%

Outcome Measures

1. Primary Outcome

Title	The Percentage of Patients Who Respond or Remit After 30 to 35 Treatments Based Off of the Montgomery-Åsberg Depression Rating Scale (MADRS)
Description	The MADRS is a clinician rated scale measuring depression severity, consisting of 10 items, each scored from 0 (normal) to 6 (severe), for a total possible score of 60; higher scores denote greater severity. A decrease in MADRS score of at lease 50% will be considered a response to treatment. A MADRS score of less than 10 will be considered remission.
Time Frame	Up to 7 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients With Bipolar (I or II) Depression
Arm/Group Description	Adults with bipolar (I or II) depression, per DSM-5 criteria, were recruited at Sheppard Pratt and Mayo Clinic between December 2015 -February 2020 for TMS. Standardized treatment protocols employed 6 weeks of 10 Hz TMS to the left dorsolateral prefrontal cortex at 120% of motor threshold with 3,000 pulses per session in 4 second trains with intertrain intervals of 26 seconds. All patients were treated concurrently with a mood stabilizer. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale (MADRS). Response and remission were defined as MADRS score reductions of ≥ 50% or score ≤10, respectively. We examined response, remission, and potential contributing factors with multivariate and logistic regression models.
Measure Participants	31
Number meeting criteria	27 87.1%
Number of non-responders	4 12.9%
Number meeting criteria	23 74.2%
Number of non-responders	8 25.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Patients With Bipolar (I or II) Depression
	Comments	Paired t-test of pre and post treatment scores on MADRS
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Paired t test for pre and post treatment scores for all subjects
	Method	t-test, 2 sided
	Comments

2. Primary Outcome

Title	The Percentage of Patients Who Meet Criteria for Onset of Manic Symptoms Based on the Young Mania Rating Scale (YMRS).
Description	The Young Mania Rating Scale (YMRS) is used to determine the severity of a patient's mania. The score for the YMRS ranges form 0 to 60. Scores of 13-19 indicate minimal manic symptoms, 20-25 is mild mania, 26-37 is moderate mania, and 38-60 is severe mania. A YMRS score of 14 or greater will be used for criteria of onset of manic symptoms. The patients will be separated based on their diagnostic category of either Bipolar I Disorder or Bipolar II Disorder.
Time Frame	Up to 7 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients With Bipolar (I or II) Depression
Arm/Group Description	Adults with bipolar (I or II) depression, per DSM-5 criteria, were recruited at Sheppard Pratt and Mayo Clinic between December 2015 -February 2020 for TMS. Standardized treatment protocols employed 6 weeks of 10 Hz TMS to the left dorsolateral prefrontal cortex at 120% of motor threshold with 3,000 pulses per session in 4 second trains with intertrain intervals of 26 seconds. All patients were treated concurrently with a mood stabilizer. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale (MADRS). Response and remission were defined as MADRS score reductions of ≥ 50% or score ≤10, respectively. We examined response, remission, and potential contributing factors with multivariate and logistic regression models.
Measure Participants	31
Bipolar I Disorder	20 64.5%
Bipolar II Disorder	11 35.5%
Bipolar I Participants with Onset of Maniac Symptoms	0 0%
Bipolar II Participants with Onset of Maniac Symptoms	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Patients With Bipolar (I or II) Depression
	Comments
	Type of Statistical Test	Other
	Comments	Descriptive Frequencies Analysis
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		A frequencies analysis was conducted to determine the number of participants that were diagnosed with BP I and BP II as well as the number of participants that developed an onset of maniac symptoms during the 7 week treatment period.

3. Secondary Outcome

Title	Hamilton Depression Rating Scale (HAM-D) to Calculate Percentage of Patients Meeting Response Criteria
Description	The Hamilton Depression (HAM-D) Rating Scale is a scale used to measure one's depression. The scoring from the scale ranges 0 to 53. Higher scores indicate that a person is more depressed. The scoring ranges from 0-7 is normal, 8-13 is mild depression, 14-18 is moderate depression, 19-22 severe depression, and greater than or equal to 23 is very severe depression. The HAM-D response criteria will be based off a HAM-D score drop of at least 50%. Remission HAM-D score will be 7 or less.
Time Frame	Up to 7 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients With Bipolar (I or II) Depression
Arm/Group Description	Adults with bipolar (I or II) depression, per DSM-5 criteria, were recruited at Sheppard Pratt and Mayo Clinic between December 2015 -February 2020 for TMS. Standardized treatment protocols employed 6 weeks of 10 Hz TMS to the left dorsolateral prefrontal cortex at 120% of motor threshold with 3,000 pulses per session in 4 second trains with intertrain intervals of 26 seconds. All patients were treated concurrently with a mood stabilizer. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale (MADRS). Response and remission were defined as MADRS score reductions of ≥ 50% or score ≤10, respectively. We examined response, remission, and potential contributing factors with multivariate and logistic regression models.
Measure Participants	31
Remission : Met criteria	21 67.7%
Remission : Non-responders	10 32.3%
Response : Met criteria	24 77.4%
Response : Non-responders	7 22.6%

4. Secondary Outcome

Title	Clinical Global Impression (CGI) to Calculate Percentage of Patients Meeting Response Criteria
Description	The Clinical Global Impression (CGI) Scale is used to determine the severity of a patient's depression. The scoring for the scale ranges from 1 to 7, where 1 indicates that the patient is normal and 7 indicates a severe depression. Remission criteria for the CGI score will be a 2 or less. Responders and remitters will also be followed for six months after the final treatment to see the durability of response. Percentage of patients' meeting relapse criteria will be calculated.
Time Frame	Up to 7 weeks and 6 Month Follow Up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients With Bipolar (I or II) Depression
Arm/Group Description	Adults with bipolar (I or II) depression, per DSM-5 criteria, were recruited at Sheppard Pratt and Mayo Clinic between December 2015 -February 2020 for TMS. Standardized treatment protocols employed 6 weeks of 10 Hz TMS to the left dorsolateral prefrontal cortex at 120% of motor threshold with 3,000 pulses per session in 4 second trains with intertrain intervals of 26 seconds. All patients were treated concurrently with a mood stabilizer. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale (MADRS). Response and remission were defined as MADRS score reductions of ≥ 50% or score ≤10, respectively. We examined response, remission, and potential contributing factors with multivariate and logistic regression models.
Measure Participants	31
Met criteria	27 87.1%
Did not meet criteria	4 12.9%
Met criteria	9 29%
Did not meet criteria	22 71%

5. Secondary Outcome

Title	Hamilton Depression Rating Scale (HAM-D) to Average Number of Treatments Needed to Meet Remission
Description	For the patients meeting remission criteria (Total Number = 21) , we will calculate the number of treatments required to achieve remission. Patients who only meet response criteria will be treated for 30 to 35 sessions.
Time Frame	7 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients With Bipolar (I or II) Depression
Arm/Group Description	Adults with bipolar (I or II) depression, per DSM-5 criteria, were recruited at Sheppard Pratt and Mayo Clinic between December 2015 -February 2020 for TMS. Standardized treatment protocols employed 6 weeks of 10 Hz TMS to the left dorsolateral prefrontal cortex at 120% of motor threshold with 3,000 pulses per session in 4 second trains with intertrain intervals of 26 seconds. All patients were treated concurrently with a mood stabilizer. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale (MADRS). Response and remission were defined as MADRS score reductions of ≥ 50% or score ≤10, respectively. We examined response, remission, and potential contributing factors with multivariate and logistic regression models.
Measure Participants	21
Mean (Standard Deviation) [Number of Treatments]	25.76 (5.02)

6. Secondary Outcome

Title	Clinical Global Impression (CGI) to Calculate Average Number of Treatments Needed to Meet Remission
Description	For the patients meeting remission criteria (Total Number = 27) , we will calculate the number of treatments required to achieve remission. Patients who only meet response criteria will be treated for 30 to 35 sessions.
Time Frame	7 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients With Bipolar (I or II) Depression
Arm/Group Description	Adults with bipolar (I or II) depression, per DSM-5 criteria, were recruited at Sheppard Pratt and Mayo Clinic between December 2015 -February 2020 for TMS. Standardized treatment protocols employed 6 weeks of 10 Hz TMS to the left dorsolateral prefrontal cortex at 120% of motor threshold with 3,000 pulses per session in 4 second trains with intertrain intervals of 26 seconds. All patients were treated concurrently with a mood stabilizer. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale (MADRS). Response and remission were defined as MADRS score reductions of ≥ 50% or score ≤10, respectively. We examined response, remission, and potential contributing factors with multivariate and logistic regression models.
Measure Participants	27
Mean (Standard Deviation) [Number of Treatments]	26.48 (4.45)

Adverse Events

Time Frame	Six months
Arm/Group Title	Patients With Bipolar (I or II) Depression
Arm/Group Description	Thirty-one adults (13M/18F; age: 42.2[14.3]) with bipolar (I or II) depression, per DSM-5 criteria, were recruited at Sheppard Pratt and Mayo Clinic between December 2015-February 2020 for TMS. Standardized treatment protocols employed 6 weeks of 10 Hz TMS to the left dorsolateral prefrontal cortex at 120% of motor threshold with 3,000 pulses per session in 4 second trains with intertrain intervals of 26 seconds. All patients were treated concurrently with a mood stabilizer. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale (MADRS). Response and remission were defined as MADRS score reductions of ≥ 50% or score ≤10, respectively. We examined response, remission, and potential contributing factors with multivariate and logistic regression models.
All Cause Mortality
	Patients With Bipolar (I or II) Depression
	Affected / at Risk (%)	# Events
Total	0/31 (0%)
Serious Adverse Events
	Patients With Bipolar (I or II) Depression
	Affected / at Risk (%)	# Events
Total	0/31 (0%)
Other (Not Including Serious) Adverse Events
	Patients With Bipolar (I or II) Depression
	Affected / at Risk (%)	# Events
Total	1/31 (3.2%)
Psychiatric disorders
Agitation	1/31 (3.2%)	1

Limitations/Caveats

Open label trial

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.