Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression: OL Cohort

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

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03240692

Acronym

SAINT-TRD

Enrollment

Registered

2017-08-07

Start date

2017-05-01

Completion date

2020-03-03

Last updated

2022-04-21

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Treatment Resistant Depression

Keywords

Major Depressive Disorder, Treatment-Resistant Depression, Transcranial Magnetic Stimulation (TMS), Theta-Burst Stimulation

Brief summary

This study evaluates an accelerated schedule of theta-burst stimulation using a transcranial magnetic stimulation device for treatment-resistant depression. In this open label study, all participants will receive accelerated theta-burst stimulation.

Detailed description

Repetitive transcranial magnetic stimulation (rTMS) is an established technology as therapy for treatment-resistant depression. The approved method for treatment is 10Hz stimulation for 40 minutes over the left dorsolateral prefrontal cortex (L-DLPFC) for a 6 week treatment course. This methodology has been successful for many people with treatment-resistant depression. One of the limitations of this approach is the long duration of the treatment course (approximately a 6 weeks per treatment course). Recently, researchers have aggressively pursued modifying the treatment parameters to reduce treatment course time with some preliminary success. This study intends to further modify the parameters to create a more rapid form of the treatment. This study will also look at the change in neuroimaging biomarkers associated with this treatment.

Interventions

DEVICEAccelerated theta-burst stimulation treatment

All participants will receive intermittent theta-burst stimulation (iTBS) to the left dorsal lateral prefrontal cortex (L-DLPFC). The L-DLPFC will be targeted utilizing the Localite neuronavigation system. Stimulation intensity will be standardized at 90% of resting motor threshold (adjusted for cortical depth). Stimulation will be delivered to L-DLPFC using the Magventure Magpro X100 and/or the NextStim TMS system.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

22 Years to 80 Years

Healthy volunteers

Inclusion criteria

* Male or female, 22 to 80 years of age. * Able to provide informed consent. * Diagnosed with Major Depressive Disorder (MDD) and currently experiencing a Major Depressive Episode (MDE). * Participants may currently be on a stable and adequate dose of an antidepressant therapy but the medication must remain stable throughout study enrollment. * Participants may also have a history of intolerance to antidepressant medications. These patients with the intolerance history will not be required to be currently taking an antidepressant medication. * Meet the threshold on the total HAMD17 score of \>/=20 at both screening and baseline visits (Day -5/-14 and Day 0). * Meet the threshold on the total MADRS score of \>/=20 at both screening and baseline visits (Day -5/-14 and Day 0). * Meet the threshold on the total BDI-II score of \>/=20 at both screening and baseline visits (Day -5/-14 and Day 0). * In good general health, as ascertained by medical history. * If female, a status of non-childbearing potential or use of an acceptable form of birth control. * Concurrent hypnotic therapy (e.g., with zolpidem, zaleplon, melatonin, or trazodone) will be allowed if the therapy has been stable for at least 4 weeks prior to screening and if it is expected to remain stable. * History of ECT intolerance is permitted.

Exclusion criteria

* Female of childbearing potential who is not willing to use one of the specified forms of birth control during the study. * Female that is pregnant or breastfeeding. * Total HAMD score of \< 20 at the screen or baseline visits. * Total MADRS score of \< 20 at the screen or baseline visits. * Total BDI-II score of \< 20 at the screen or baseline visits. * Current diagnosis of a Substance Use Disorder (Abuse or Dependence, as defined by DSM-IV-TR), with the exception of nicotine dependence. * Current diagnosis of Axis I disorders other than Dysthymic Disorder, Generalized Anxiety Disorder, Social Anxiety Disorder, Panic Disorder, Agoraphobia, or Specific Phobia (unless one of these is comorbid and clinically unstable, and/or the focus of the participant's treatment for the past six months or more). * History of schizophrenia or schizoaffective disorders, or any history of psychotic symptoms in the current or previous depressive episodes. * Any Axis I or Axis II Disorder, which at screening is clinically predominant to their MDD or has been predominant to their MDD at any time within six months prior to screening. * Has a clinically significant abnormality on the screening examination that might affect safety, study participation, or confound interpretation of study results. * Participation in any clinical trial with an investigational drug or device within the past month or concurrent to study participation. * Any current or past history of any physical condition which in the investigator's opinion might put the subject at risk or interfere with study results interpretation. * Positive screening on the urine test for drugs of abuse at screening: cocaine, amphetamines, barbiturates, opiates. * Current (or chronic) use of opiates. * History of epilepsy. * History of shrapnel or metal in the head or skull. * History of cardiovascular disease or cardiac event. * History of OCD. * History of autism spectrum disorder. * History of rTMS exposure

Design outcomes

Primary

Measure	Time frame	Description
Percent Change in the Montgomery Asberg Depression Rating Scale (MADRS) Score From Pre-treatment to 1-month	Pre-treatment and 1-month post treatment.	A ten item diagnostic questionnaire used to measure the severity of depressive symptoms in patients with mood disorders. Scale range - 0 to 60 with higher score indicative of greater depressive symptomology.

Secondary

Measure	Time frame	Description
Percent Change in the Columbia Suicide Severity Rating Scale (C-SSRS)	Pre-treatment to immediately post-treatment (on day 5) and 4 weeks post-treatment	A suicidal ideation rating scale created by researchers at Columbia University. The score was calculated by summing the answers to 5 questions. Score range - 0 to 5. Higher score indicate higher suicidal ideation.
Percent Change in the Hamilton Rating Scale for Depression (HAM-6)	Pre-treatment to immediately post-treatment (on day 5) and 2 weeks,4 weeks and 6 weeks post-treatment	A 6 item questionnaire used to score the severity of depression. Scale range - 0 to 22 with higher score indicative of greater depressive symptomology. Additional collection time points were pre-specified; only those time points for which data were collected are reported.
Percent Change in the Hamilton Rating Scale for Depression (HAM-17)	Pre-treatment to immediately post-treatment (on day 5) and 2 weeks, 4 weeks, 6 weeks and 8 weeks post-treatment	A provider administered questionnaire used to assess remission and recovery from depression. Scale range - 0 to 52 with higher score indicative of greater depressive symptomology. Additional collection time points were pre-specified; only those time points for which data were collected are reported.
Percent Change in the Beck Depression Inventory (BDI-II)	Pretreatment to immediately post-treatment (on day 5) and 2 weeks, 4 weeks, 6 weeks and 8 weeks post treatment.	A 21 item Self-report measure of depressive symptoms. Scale range - 0 to 63 with higher score indicative of greater depressive symptomology. Additional collection time points were pre-specified; only those time points for which data were collected are reported.
Percent Change in the Montgomery Asberg Depression Rating Scale (MADRS)	Pre-treatment to immediately post treatment (on day 5) and 2 weeks, 4 weeks and 8 weeks post-treatment	A ten item diagnostic questionnaire used to measure the severity of depressive symptoms in patients with mood disorders. Scale range - 0 to 60 with higher score indicative of greater depressive symptomology. Additional collection time points were pre-specified; only those time points for which data were collected are reported.
Change From Baseline Functional Connectivity to Immediately Post-treatment	Pre-treatment to immediately post treatment (on day 5).	Within subject changes in resting state functional connectivity of subgenual anterior cingulate cortex (sgACC) to default mode network (DMN). frontal (f)DMN (medial prefrontal cortex), median (m)DMN (posterior cingulate cortex and precuneus), left (l)DMN (left angular gyrus), right (r)DMN (right angular gyrus). T-statistic (T-score): ratio of departure of estimated value from its hypothesized value to its standard error used in a t-test to determine whether to support or reject the null hypothesis. A T-score of ≥ 2.11 or ≤ -2.11 would be considered a statistically significant change if the accompanying p-value (subject to false discovery rate correction of multiple comparisons) was ≤ 0.05. Positive T-score = increased connectivity, negative T-score = decreased connectivity. No established reference range or clinically meaningful threshold exists for this patient population. Higher connectivity between all DMN nodes to sgACC has been found in depressed vs healthy population.
Change From Baseline Functional Connectivity to 1-month Post-treatment	Pre-treatment, immediately post-treatment (on day 5), 1-month post-treatment	We will assess change in resting state fMRI functional connectivity of the subcallosal cingulate to the default mode network and within the default mode network.

Other

Measure	Time frame	Description
A Neuropsychological Test Battery Testing Cognitive Abilities	Pre-treatment, immediately post-treatment (on day 5) and 4 weeks post-treatment	The Hopkins Verbal Learning Test - Revised (HVLT-DR). Score range 0 to 72, higher score indicates better verbal learning. The Brief Visuospatial Memory Test - Revised (BVMT-DR). Score range 0 to 84, higher score indicates better visuospatial memory. Digit Span test and various tests from the Delis Kaplan Executive Function System (DKEFS) will be used to assess possible cognitive side-effects. Score range 0-36, higher score indicates better executive functions.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Accelerated Theta Burst Treatment All participants will receive theta-burst TMS. Accelerated theta-burst stimulation treatment: All participants will receive intermittent theta-burst stimulation (iTBS) to the left dorsal lateral prefrontal cortex (L-DLPFC). The L-DLPFC will be targeted utilizing the Localite neuronavigation system. Stimulation intensity will be standardized at 90% of resting motor threshold (adjusted for cortical depth). Stimulation will be delivered to L-DLPFC using the Magventure Magpro X100 and/or the NextStim TMS system.	21
Total	21

Arm

Count

Accelerated Theta Burst Treatment

All participants will receive theta-burst TMS. Accelerated theta-burst stimulation treatment: All participants will receive intermittent theta-burst stimulation (iTBS) to the left dorsal lateral prefrontal cortex (L-DLPFC). The L-DLPFC will be targeted utilizing the Localite neuronavigation system. Stimulation intensity will be standardized at 90% of resting motor threshold (adjusted for cortical depth). Stimulation will be delivered to L-DLPFC using the Magventure Magpro X100 and/or the NextStim TMS system.

Total

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Physician Decision	1
Overall Study	Withdrawal by Subject	1

Baseline characteristics

Characteristic	Accelerated Theta Burst Treatment	—
Age, Categorical <=18 years	0 Participants	—
Age, Categorical >=65 years	4 Participants	—
Age, Categorical Between 18 and 65 years	17 Participants	—
Age, Continuous	44.86 years STANDARD_DEVIATION 17.21	—
Beck Depression Inventory (BDI-II)	28.78 Scores on a scale. STANDARD_DEVIATION 11.68	—
Columbia Suicide Severity Rating Scale (C-SSRS)	1.42 Scores on a scale. STANDARD_DEVIATION 0.96	—
Hamilton Rating Scale for Depression (HAM-17)	25.90 Scores on a scale. STANDARD_DEVIATION 4.79	—
Hamilton Rating Scale for Depression (HAM-6)	13.90 Scores on a scale. STANDARD_DEVIATION 2.45	—
Montgomery Asberg Depression Rating Scale (MADRS) Score	34.86 Scores on a scale. STANDARD_DEVIATION 5.29	—
Race and Ethnicity Not Collected	—	— Participants
Region of Enrollment United States	21 Participants	—
Sex: Female, Male Female	12 Participants	—
Sex: Female, Male Male	9 Participants	—

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 23
other Total, other adverse events	0 / 23
serious Total, serious adverse events	0 / 23

Outcome results

Primary

Percent Change in the Montgomery Asberg Depression Rating Scale (MADRS) Score From Pre-treatment to 1-month

Time frame: Pre-treatment and 1-month post treatment.

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

Arm	Measure	Value (MEAN)	Dispersion
Accelerated Theta Burst Treatment	Percent Change in the Montgomery Asberg Depression Rating Scale (MADRS) Score From Pre-treatment to 1-month	-67.07 Percentage of change in score	Standard Deviation 34.71

Secondary

Change From Baseline Functional Connectivity to 1-month Post-treatment

We will assess change in resting state fMRI functional connectivity of the subcallosal cingulate to the default mode network and within the default mode network.

Time frame: Pre-treatment, immediately post-treatment (on day 5), 1-month post-treatment

Population: Data analysis was not possible due to missing data and poor image quality (unable to read)

Secondary

Change From Baseline Functional Connectivity to Immediately Post-treatment

Within subject changes in resting state functional connectivity of subgenual anterior cingulate cortex (sgACC) to default mode network (DMN). frontal (f)DMN (medial prefrontal cortex), median (m)DMN (posterior cingulate cortex and precuneus), left (l)DMN (left angular gyrus), right (r)DMN (right angular gyrus). T-statistic (T-score): ratio of departure of estimated value from its hypothesized value to its standard error used in a t-test to determine whether to support or reject the null hypothesis. A T-score of ≥ 2.11 or ≤ -2.11 would be considered a statistically significant change if the accompanying p-value (subject to false discovery rate correction of multiple comparisons) was ≤ 0.05. Positive T-score = increased connectivity, negative T-score = decreased connectivity. No established reference range or clinically meaningful threshold exists for this patient population. Higher connectivity between all DMN nodes to sgACC has been found in depressed vs healthy population.

Time frame: Pre-treatment to immediately post treatment (on day 5).

Population: Participants who provided data for the respective time point are included in the analysis

Arm	Measure	Group	Value (NUMBER)
Accelerated Theta Burst Treatment	Change From Baseline Functional Connectivity to Immediately Post-treatment	sgACC-fDMN	-2.335 T-score
Accelerated Theta Burst Treatment	Change From Baseline Functional Connectivity to Immediately Post-treatment	sgACC-mDMN	-3.027 T-score
Accelerated Theta Burst Treatment	Change From Baseline Functional Connectivity to Immediately Post-treatment	sgACC-lDMN	-2.106 T-score
Accelerated Theta Burst Treatment	Change From Baseline Functional Connectivity to Immediately Post-treatment	sgACC-rDMN	-2.660 T-score

Comparison: Analysis of subgenual Anterior Cingulate Cortex (sgACC) and frontal Default Mode Network (fDMN) functional connectivityp-value: 0.036t-test, 2 sided

Comparison: Analysis of subgenual Anterior Cingulate Cortex (sgACC) and medial Default Mode Network (mDMN) functional connectivityp-value: 0.008t-test, 2 sided

Comparison: Analysis of subgenual Anterior Cingulate Cortex (sgACC) and left Default Mode Network (lDMN) functional connectivity.p-value: 0.06t-test, 2 sided

Comparison: Analysis of subgenual Anterior Cingulate Cortex (sgACC) and right Default Mode Network (rDMN) functional connectivity.p-value: 0.017t-test, 2 sided

Secondary

Percent Change in the Beck Depression Inventory (BDI-II)

A 21 item Self-report measure of depressive symptoms. Scale range - 0 to 63 with higher score indicative of greater depressive symptomology. Additional collection time points were pre-specified; only those time points for which data were collected are reported.

Time frame: Pretreatment to immediately post-treatment (on day 5) and 2 weeks, 4 weeks, 6 weeks and 8 weeks post treatment.