Trial Outcomes & Findings for Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression (SAINT-TRD) (NCT NCT03068715)

Last Updated: 2022-05-18

Results Overview

A ten item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders.The MADRS has an overall score range from 0-60, with higher scores corresponding to higher levels of depression.

Recruitment status

COMPLETED

Study phase

Target enrollment

30 participants

Primary outcome timeframe

Pretreatment (baseline), 1-month post-treatment

Results posted on

2022-05-18

Participant Flow

Participant milestones

Participant milestones
Measure	Active TBS-DLPFC The active group will receive theta-burst TMS stimulation. Active TBS-DLPFC: Participants in the active stimulation group will receive intermittent TBS to left DLPFC. The L-DLPFC will be targeted utilizing the Localite neuronavigation system. Stimulation intensity will be standardized at 90% of RMT and adjusted to the skull to cortical surface distance (see Nahas 2004). Stimulation will be delivered to the L-DLPFC using a MagPro stimulator. Open label TBS-DLPFC: All patients will have the option to receive active, open label aTBS treatment after the 1-month mark, following the blinded phase. Stimulation will be delivered to the L-DLPFC using a MagPro stimulator or Nexstim TMS device.	Sham TBS-DLPFC The sham group will receive sham theta-burst TMS stimulation. Sham TBS-DLPFC: The parameters in the active arms will be as above with the internal randomization of the device internally switching to sham in a blinded fashion. Open label TBS-DLPFC: All patients will have the option to receive active, open label aTBS treatment after the 1-month mark, following the blinded phase. Stimulation will be delivered to the L-DLPFC using a MagPro stimulator or Nexstim TMS device.
Overall Study STARTED	15	15
Overall Study COMPLETED	14	15
Overall Study NOT COMPLETED	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Active TBS-DLPFC The active group will receive theta-burst TMS stimulation. Active TBS-DLPFC: Participants in the active stimulation group will receive intermittent TBS to left DLPFC. The L-DLPFC will be targeted utilizing the Localite neuronavigation system. Stimulation intensity will be standardized at 90% of RMT and adjusted to the skull to cortical surface distance (see Nahas 2004). Stimulation will be delivered to the L-DLPFC using a MagPro stimulator. Open label TBS-DLPFC: All patients will have the option to receive active, open label aTBS treatment after the 1-month mark, following the blinded phase. Stimulation will be delivered to the L-DLPFC using a MagPro stimulator or Nexstim TMS device.	Sham TBS-DLPFC The sham group will receive sham theta-burst TMS stimulation. Sham TBS-DLPFC: The parameters in the active arms will be as above with the internal randomization of the device internally switching to sham in a blinded fashion. Open label TBS-DLPFC: All patients will have the option to receive active, open label aTBS treatment after the 1-month mark, following the blinded phase. Stimulation will be delivered to the L-DLPFC using a MagPro stimulator or Nexstim TMS device.
Overall Study No longer met inclusion criteria	1	0

Baseline Characteristics

Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression (SAINT-TRD)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Active TBS-DLPFC n=14 Participants The active group will receive theta-burst TMS stimulation. Active TBS-DLPFC: Participants in the active stimulation group will receive intermittent TBS to left DLPFC. The L-DLPFC will be targeted utilizing the Localite neuronavigation system. Stimulation intensity will be standardized at 90% of RMT and adjusted to the skull to cortical surface distance (see Nahas 2004). Stimulation will be delivered to the L-DLPFC using a MagPro stimulator.	Sham TBS-DLPFC n=15 Participants The sham group will receive sham theta-burst TMS stimulation. Sham TBS-DLPFC: The parameters in the active arms will be as above with the internal randomization of the device internally switching to sham in a blinded fashion.	Total n=29 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Age, Categorical Between 18 and 65 years	11 Participants n=93 Participants	11 Participants n=4 Participants	22 Participants n=27 Participants
Age, Categorical >=65 years	3 Participants n=93 Participants	4 Participants n=4 Participants	7 Participants n=27 Participants
Age, Continuous	49 years n=93 Participants	52 years n=4 Participants	51 years n=27 Participants
Sex: Female, Male Female	5 Participants n=93 Participants	5 Participants n=4 Participants	10 Participants n=27 Participants
Sex: Female, Male Male	9 Participants n=93 Participants	10 Participants n=4 Participants	19 Participants n=27 Participants
Race/Ethnicity, Customized White	12 Participants n=93 Participants	13 Participants n=4 Participants	25 Participants n=27 Participants
Race/Ethnicity, Customized Asian	2 Participants n=93 Participants	1 Participants n=4 Participants	3 Participants n=27 Participants
Race/Ethnicity, Customized Other	0 Participants n=93 Participants	1 Participants n=4 Participants	1 Participants n=27 Participants
Region of Enrollment United States	14 participants n=93 Participants	15 participants n=4 Participants	29 participants n=27 Participants
Years of education	17 years n=93 Participants	17 years n=4 Participants	17 years n=27 Participants
Currently employed	7 Participants n=93 Participants	6 Participants n=4 Participants	13 Participants n=27 Participants
Duration of illness	30 years n=93 Participants	23 years n=4 Participants	26 years n=27 Participants
Duration of current depressive episode	8 years n=93 Participants	10 years n=4 Participants	9 years n=27 Participants
ATHF adequate antidepressant trials, lifetime	5 number of lifetime antidepressant trials n=93 Participants	5 number of lifetime antidepressant trials n=4 Participants	5 number of lifetime antidepressant trials n=27 Participants
ATHF adequate augmentation trials, lifetime	1 number of lifetime augmentation trials n=93 Participants	1 number of lifetime augmentation trials n=4 Participants	1 number of lifetime augmentation trials n=27 Participants
ATHF adequate antidepressant trials, current episode	2 number of current antidepressant trials n=93 Participants	1 number of current antidepressant trials n=4 Participants	2 number of current antidepressant trials n=27 Participants
ATHF adequate augmentation trials, current episode	1 number of current augmentation trials n=93 Participants	0 number of current augmentation trials n=4 Participants	0 number of current augmentation trials n=27 Participants
Maudsley Staging Method Score	9 score on a scale n=93 Participants	9 score on a scale n=4 Participants	9 score on a scale n=27 Participants
Baseline MADRS overall score	31 score on a scale n=93 Participants	35 score on a scale n=4 Participants	33 score on a scale n=27 Participants
Baseline HAM-6 score	14 score on a scale n=93 Participants	15 score on a scale n=4 Participants	15 score on a scale n=27 Participants

PRIMARY outcome

Timeframe: Pretreatment (baseline), 1-month post-treatment

Population: Participants who completed the protocol are included in the analysis.

Outcome measures

Outcome measures
Measure	Active TBS-DLPFC n=14 Participants The active group will receive theta-burst TMS stimulation. Active TBS-DLPFC: Participants in the active stimulation group will receive intermittent TBS to left DLPFC. The L-DLPFC will be targeted utilizing the Localite neuronavigation system. Stimulation intensity will be standardized at 90% of RMT and adjusted to the skull to cortical surface distance (see Nahas 2004). Stimulation will be delivered to the L-DLPFC using a MagPro stimulator.	Sham TBS-DLPFC n=15 Participants The sham group will receive sham theta-burst TMS stimulation. Sham TBS-DLPFC: The parameters in the active arms will be as above with the internal randomization of the device internally switching to sham in a blinded fashion.
Percentage Change in Montgomery-Åsberg Depression Rating Scale (MADRS) Score From Pre-treatment to 1-month Post-treatment.	-53 percent change in MADRS score Standard Deviation 35	-11 percent change in MADRS score Standard Deviation 29

SECONDARY outcome

Timeframe: pre-treatment (baseline) to 1-month post-treatment

Population: Participants who completed the protocol are included in the analysis.

A provider administered questionnaire used to assess remission and recovery from depression. The HAMD-17 is a 17-item questionnaire to assess depression severity. Each item is scored from 0-4, with higher scores representing increasing depression severity.

Outcome measures

Outcome measures
Measure	Active TBS-DLPFC n=14 Participants The active group will receive theta-burst TMS stimulation. Active TBS-DLPFC: Participants in the active stimulation group will receive intermittent TBS to left DLPFC. The L-DLPFC will be targeted utilizing the Localite neuronavigation system. Stimulation intensity will be standardized at 90% of RMT and adjusted to the skull to cortical surface distance (see Nahas 2004). Stimulation will be delivered to the L-DLPFC using a MagPro stimulator.	Sham TBS-DLPFC n=15 Participants The sham group will receive sham theta-burst TMS stimulation. Sham TBS-DLPFC: The parameters in the active arms will be as above with the internal randomization of the device internally switching to sham in a blinded fashion.
Percentage Change in the Hamilton Rating Scale for Depression (HAMD-17)	-52 percent change in HAM-17 score Standard Deviation 29	-12 percent change in HAM-17 score Standard Deviation 27

SECONDARY outcome

Timeframe: Pretreatment (baseline) to immediately post-treatment (day 8).

Population: Participants with available data are included in this analysis. Only participants with paired data are included.

The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire used for suicide assessment developed by multiple institutions including Columbia University. Participants were asked a series of 6 yes or no questions. Yes answers indicate more suicidal ideation. Here we report a count of participants with an increase, decrease or no change in suicidal ideation.

Outcome measures

Outcome measures
Measure	Active TBS-DLPFC n=8 Participants The active group will receive theta-burst TMS stimulation. Active TBS-DLPFC: Participants in the active stimulation group will receive intermittent TBS to left DLPFC. The L-DLPFC will be targeted utilizing the Localite neuronavigation system. Stimulation intensity will be standardized at 90% of RMT and adjusted to the skull to cortical surface distance (see Nahas 2004). Stimulation will be delivered to the L-DLPFC using a MagPro stimulator.	Sham TBS-DLPFC n=6 Participants The sham group will receive sham theta-burst TMS stimulation. Sham TBS-DLPFC: The parameters in the active arms will be as above with the internal randomization of the device internally switching to sham in a blinded fashion.
Change in the Columbia Suicide Severity Rating Scale (C-SSRS) Score Increased	0 Participants	0 Participants
Change in the Columbia Suicide Severity Rating Scale (C-SSRS) Score Decreased	6 Participants	1 Participants
Change in the Columbia Suicide Severity Rating Scale (C-SSRS) Score No Change	2 Participants	5 Participants

SECONDARY outcome

Timeframe: Baseline (pre-treatment) and at 1-month post-treatment

Population: Participants with available data are included in this analysis. Only participants with paired data are included. Scores are marked as a change from baseline if the difference is greater than 1 point.

The Hamilton Depression Rating Scale (HDRS, also known as Ham-D) is the most widely used clinician-administered depression assessment scale. The Ham-6 version consists of 6 items assessing for: mood, guilt, general somatic symptoms, work and activities, anxiety and slowness of thought and speech). Each item is scored on a scale of 0 to 4, except for the somatic symptoms item, which is scored 0 to 2. On the HAM-6 there can be a total score of 22. Higher scores represent higher depression severity. Here, we report a count of participants with an overall increase, decrease or no change in total HAM-6 score. Participants with an increase in total score (row 3) would signify a worse outcome than participants with a decrease in total score.

Outcome measures

Outcome measures
Measure	Active TBS-DLPFC n=11 Participants The active group will receive theta-burst TMS stimulation. Active TBS-DLPFC: Participants in the active stimulation group will receive intermittent TBS to left DLPFC. The L-DLPFC will be targeted utilizing the Localite neuronavigation system. Stimulation intensity will be standardized at 90% of RMT and adjusted to the skull to cortical surface distance (see Nahas 2004). Stimulation will be delivered to the L-DLPFC using a MagPro stimulator.	Sham TBS-DLPFC n=10 Participants The sham group will receive sham theta-burst TMS stimulation. Sham TBS-DLPFC: The parameters in the active arms will be as above with the internal randomization of the device internally switching to sham in a blinded fashion.
Change in the Hamilton Rating Scale for Depression (HAM-6) Score No Change	2 Participants	6 Participants
Change in the Hamilton Rating Scale for Depression (HAM-6) Score Increased	1 Participants	1 Participants
Change in the Hamilton Rating Scale for Depression (HAM-6) Score Decreased	8 Participants	3 Participants

SECONDARY outcome

Timeframe: Pre-treatment (baseline) to immediately post-treatment (day 8).

Population: Participants who completed the protocol are included in the analysis.

The Hamilton Depression Rating Scale (HDRS, also known as Ham-D) is the most widely used clinician-administered depression assessment scale. The Ham-17 version consists of 17 items assessing for: mood, guilt, general somatic symptoms, work and activities, anxiety and slowness of thought and speech. Each item is scored on a scale of 0 to 4, except for the somatic, sleep and insight items which are scored 0 to 2. On the HAM-17 there can be a total score of 22. Higher scores represent higher depression severity.

Outcome measures

Outcome measures
Measure	Active TBS-DLPFC n=14 Participants The active group will receive theta-burst TMS stimulation. Active TBS-DLPFC: Participants in the active stimulation group will receive intermittent TBS to left DLPFC. The L-DLPFC will be targeted utilizing the Localite neuronavigation system. Stimulation intensity will be standardized at 90% of RMT and adjusted to the skull to cortical surface distance (see Nahas 2004). Stimulation will be delivered to the L-DLPFC using a MagPro stimulator.	Sham TBS-DLPFC n=15 Participants The sham group will receive sham theta-burst TMS stimulation. Sham TBS-DLPFC: The parameters in the active arms will be as above with the internal randomization of the device internally switching to sham in a blinded fashion.
Percentage Change in the Hamilton Rating Scale for Depression (HAMD-17)	-59 percent change in score Standard Deviation 31	-20 percent change in score Standard Deviation 22

SECONDARY outcome

Timeframe: Pretreatment (baseline) to immediately post-treatment (day 8).

Population: Participants with available data were included in the analysis.

We quantified the functional connectivity change between the subcallosal cingulate to the default mode network and within the default mode network using baseline and immediate post-treatment MRI scans. We report below, changes of functional connectivity (Fisher's Z score of Pearson correlation coefficient for each pair of ROIs) from immediately post-treatment (day 8) to baseline.

Outcome measures

Outcome measures
Measure	Active TBS-DLPFC n=13 Participants The active group will receive theta-burst TMS stimulation. Active TBS-DLPFC: Participants in the active stimulation group will receive intermittent TBS to left DLPFC. The L-DLPFC will be targeted utilizing the Localite neuronavigation system. Stimulation intensity will be standardized at 90% of RMT and adjusted to the skull to cortical surface distance (see Nahas 2004). Stimulation will be delivered to the L-DLPFC using a MagPro stimulator.	Sham TBS-DLPFC n=12 Participants The sham group will receive sham theta-burst TMS stimulation. Sham TBS-DLPFC: The parameters in the active arms will be as above with the internal randomization of the device internally switching to sham in a blinded fashion.
Change From Baseline Functional Connectivity to Immediate Post-treatment lsgACC_lDMN	0.071 Z-score Standard Deviation 0.242	0.025 Z-score Standard Deviation 0.301
Change From Baseline Functional Connectivity to Immediate Post-treatment lDMN_rDMN	-0.069 Z-score Standard Deviation 0.330	0.117 Z-score Standard Deviation 0.565

SECONDARY outcome

Timeframe: Pretreatment (baseline) to 1-month post-treatment

Population: Participants with available data were included in the analysis.

We will assess functional connectivity as seen on resting state fMRI, between the subcallosal cingulate to the default mode network and within the default mode network. We report below, changes of functional connectivity (Fisher's Z score of Pearson correlation coefficient for each pair of ROIs) from post-treatment(1m) to baseline.

Outcome measures

Outcome measures
Measure	Active TBS-DLPFC n=13 Participants The active group will receive theta-burst TMS stimulation. Active TBS-DLPFC: Participants in the active stimulation group will receive intermittent TBS to left DLPFC. The L-DLPFC will be targeted utilizing the Localite neuronavigation system. Stimulation intensity will be standardized at 90% of RMT and adjusted to the skull to cortical surface distance (see Nahas 2004). Stimulation will be delivered to the L-DLPFC using a MagPro stimulator.	Sham TBS-DLPFC n=11 Participants The sham group will receive sham theta-burst TMS stimulation. Sham TBS-DLPFC: The parameters in the active arms will be as above with the internal randomization of the device internally switching to sham in a blinded fashion.
Change From Baseline Functional Connectivity to 1-month Post-treatment lsgACC_lDMN	0.090 Z-score Standard Deviation 0.287	-0.163 Z-score Standard Deviation 0.258
Change From Baseline Functional Connectivity to 1-month Post-treatment lDMN_rDMN	-0.039 Z-score Standard Deviation 0.702	-0.056 Z-score Standard Deviation 0.388

SECONDARY outcome

Timeframe: Pretreatment to 1-month post-treatment

Population: Smaller than the total number of participants because some did not have data collected for this measure at either timepoint.

Heart rate variability measures will be compared pre-treatment and 1-month post-treatment.

Outcome measures

Outcome measures
Measure	Active TBS-DLPFC n=10 Participants The active group will receive theta-burst TMS stimulation. Active TBS-DLPFC: Participants in the active stimulation group will receive intermittent TBS to left DLPFC. The L-DLPFC will be targeted utilizing the Localite neuronavigation system. Stimulation intensity will be standardized at 90% of RMT and adjusted to the skull to cortical surface distance (see Nahas 2004). Stimulation will be delivered to the L-DLPFC using a MagPro stimulator.	Sham TBS-DLPFC n=9 Participants The sham group will receive sham theta-burst TMS stimulation. Sham TBS-DLPFC: The parameters in the active arms will be as above with the internal randomization of the device internally switching to sham in a blinded fashion.
Change in Baseline Heart Rate Variability to 1-month Post-treatment	46.609 SDNN in milliseconds Standard Error 25.262	-26.670 SDNN in milliseconds Standard Error 36.464

SECONDARY outcome

Timeframe: Pretreatment to immediate post-treatment (day 8).

Population: Data from 18 participants analyzed. Smaller than the total number of participants for this study because some participants were missing one or both of the timepoints needed for this variable.

Heart rate variability measures will be compared pre-treatment and immediately post-treatment.

Outcome measures

Outcome measures
Measure	Active TBS-DLPFC n=9 Participants The active group will receive theta-burst TMS stimulation. Active TBS-DLPFC: Participants in the active stimulation group will receive intermittent TBS to left DLPFC. The L-DLPFC will be targeted utilizing the Localite neuronavigation system. Stimulation intensity will be standardized at 90% of RMT and adjusted to the skull to cortical surface distance (see Nahas 2004). Stimulation will be delivered to the L-DLPFC using a MagPro stimulator.	Sham TBS-DLPFC n=9 Participants The sham group will receive sham theta-burst TMS stimulation. Sham TBS-DLPFC: The parameters in the active arms will be as above with the internal randomization of the device internally switching to sham in a blinded fashion.
Change in Baseline Heart Rate Variability to Immediate Post-treatment	16.226 SDNN in milliseconds Standard Error 15.245	-31.159 SDNN in milliseconds Standard Error 35.258

Adverse Events

Active TBS-DLPFC

Serious events: 0 serious events

Other events: 12 other events

Deaths: 0 deaths

Sham TBS-DLPFC

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Active TBS-DLPFC n=14 participants at risk The active group will receive theta-burst TMS stimulation. Active TBS-DLPFC: Participants in the active stimulation group will receive intermittent TBS to left DLPFC. The L-DLPFC will be targeted utilizing the Localite neuronavigation system. Stimulation intensity will be standardized at 90% of RMT and adjusted to the skull to cortical surface distance (see Nahas 2004). Stimulation will be delivered to the L-DLPFC using a MagPro stimulator.	Sham TBS-DLPFC n=15 participants at risk The sham group will receive sham theta-burst TMS stimulation. Sham TBS-DLPFC: The parameters in the active arms will be as above with the internal randomization of the device internally switching to sham in a blinded fashion.
General disorders Fatigue	57.1% 8/14 • 4 weeks	53.3% 8/15 • 4 weeks
Musculoskeletal and connective tissue disorders Neck/back discomfort	50.0% 7/14 • 4 weeks	33.3% 5/15 • 4 weeks
General disorders Discomfort at treatment site	35.7% 5/14 • 4 weeks	13.3% 2/15 • 4 weeks
Nervous system disorders Post-SAINT headache	57.1% 8/14 • 4 weeks	13.3% 2/15 • 4 weeks
Nervous system disorders Anxiety	28.6% 4/14 • 4 weeks	20.0% 3/15 • 4 weeks
General disorders Dental issues	7.1% 1/14 • 4 weeks	0.00% 0/15 • 4 weeks
Musculoskeletal and connective tissue disorders Jaw discomfort	14.3% 2/14 • 4 weeks	0.00% 0/15 • 4 weeks
General disorders Polydipsia	7.1% 1/14 • 4 weeks	0.00% 0/15 • 4 weeks

Additional Information

Dr. Nolan Williams

Stanford University

Phone: (650)800-6920

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place