Treatment Resistant Depression
Conditions
Keywords
transcranial magnetic stimulation, theta burst
Brief summary
This study evaluates an accelerated schedule of theta-burst stimulation using a transcranial magnetic stimulation device for treatment-resistant depression. In a double-blind fashion, half the participants will receive accelerated theta-burst stimulation while half will receive sham treatment.
Detailed description
Repetitive transcranial magnetic stimulation (rTMS) is an established therapy for treatment-resistant depression. The approved method for treatment is 10Hz stimulation for 40 min over the left dorsolateral prefrontal cortex (L-DLPFC). This methodology has been effective in real world situations. The limitations of this approach include the duration of the treatment (approximately 40 minutes per treatment session, 5 days per week, for 4-8 weeks). Recently, researchers have pursued modifying the treatment parameters to reduce treatment times with some preliminary successes. This study aims to further modify the parameters to create a more rapid form of the treatment and look at the change in neuroimaging biomarkers.
Interventions
DEVICEActive 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.
DEVICESham 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.
DEVICEOpen 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.
Sponsors
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
22 Years to 80 Years
Healthy volunteers
No
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 SSRI antidepressant therapy. Participants may choose to not be on antidepressant therapy for the study duration, or to be switched from other classes to a medication from the SSRI class. * Participants may also have a history of intolerance to at least 2 antidepressant medications. These patients with the intolerance history will not be required to be currently taking an antidepressant medication. * Participants must qualify as Moderately Treatment Refractory or High Treatment Refractory using the Maudsley staging method. * 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. The form of birth control will be documented at screening and baseline. * 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.
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. * Female with a positive pregnancy test at participation. * Total HAMD17 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, at screening or within six months prior to screening. * 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. * Considered at significant risk for suicide during the course of the study. * Cognitive impairment (as noted by previous diagnoses-including dementia). * 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. * History of positive screening urine test for drugs of abuse at screening: cocaine, amphetamines, barbiturates, opiates. * Current (or chronic) use of opiates. * History of epilepsy. * History of rTMS exposure. * History of any implanted device or psychosurgery for depression. * Any history of ECT (greater than 8 sessions) without meeting responder criteria * History of shrapnel or metal in the head or skull. * Low Treatment Refractory using the Maudsley staging method. * History of cardiovascular disease or cardiac event. * History of OCD. * History of autism spectrum disorder. * History of intractable migraine * History of independent sleep disorder.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Montgomery-Åsberg Depression Rating Scale (MADRS) Score From Pre-treatment to 1-month Post-treatment. | Pretreatment (baseline), 1-month post-treatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Columbia Suicide Severity Rating Scale (C-SSRS) Score | Pretreatment (baseline) to immediately post-treatment (day 8). | 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. |
| Change in the Hamilton Rating Scale for Depression (HAM-6) Score | Baseline (pre-treatment) and at 1-month post-treatment | 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. |
| Change From Baseline Functional Connectivity to Immediate Post-treatment | Pretreatment (baseline) to immediately post-treatment (day 8). | 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. |
| Percentage Change in the Hamilton Rating Scale for Depression (HAMD-17) | pre-treatment (baseline) to 1-month post-treatment | 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. |
| Change in Baseline Heart Rate Variability to 1-month Post-treatment | Pretreatment to 1-month post-treatment | Heart rate variability measures will be compared pre-treatment and 1-month post-treatment. |
| Change in Baseline Heart Rate Variability to Immediate Post-treatment | Pretreatment to immediate post-treatment (day 8). | Heart rate variability measures will be compared pre-treatment and immediately post-treatment. |
| Change From Baseline Functional Connectivity to 1-month Post-treatment | Pretreatment (baseline) to 1-month post-treatment | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 14 |
| 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. | 15 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | No longer met inclusion criteria | 1 | 0 |
Baseline characteristics
| Characteristic | Active TBS-DLPFC | Sham TBS-DLPFC | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 4 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 11 Participants | 22 Participants |
| Age, Continuous | 49 years | 52 years | 51 years |
| ATHF adequate antidepressant trials, current episode | 2 number of current antidepressant trials | 1 number of current antidepressant trials | 2 number of current antidepressant trials |
| ATHF adequate antidepressant trials, lifetime | 5 number of lifetime antidepressant trials | 5 number of lifetime antidepressant trials | 5 number of lifetime antidepressant trials |
| ATHF adequate augmentation trials, current episode | 1 number of current augmentation trials | 0 number of current augmentation trials | 0 number of current augmentation trials |
| ATHF adequate augmentation trials, lifetime | 1 number of lifetime augmentation trials | 1 number of lifetime augmentation trials | 1 number of lifetime augmentation trials |
| Baseline HAM-6 score | 14 score on a scale | 15 score on a scale | 15 score on a scale |
| Baseline MADRS overall score | 31 score on a scale | 35 score on a scale | 33 score on a scale |
| Currently employed | 7 Participants | 6 Participants | 13 Participants |
| Duration of current depressive episode | 8 years | 10 years | 9 years |
| Duration of illness | 30 years | 23 years | 26 years |
| Maudsley Staging Method Score | 9 score on a scale | 9 score on a scale | 9 score on a scale |
| Race/Ethnicity, Customized Asian | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 12 Participants | 13 Participants | 25 Participants |
| Region of Enrollment United States | 14 participants | 15 participants | 29 participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Male | 9 Participants | 10 Participants | 19 Participants |
| Years of education | 17 years | 17 years | 17 years |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 15 |
| other Total, other adverse events | 12 / 14 | 11 / 15 |
| serious Total, serious adverse events | 0 / 14 | 0 / 15 |
Outcome results
Primary
Percentage Change in Montgomery-Åsberg Depression Rating Scale (MADRS) Score From Pre-treatment to 1-month Post-treatment.
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.
Time frame: Pretreatment (baseline), 1-month post-treatment
Population: Participants who completed the protocol are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active TBS-DLPFC | 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 |
| Sham TBS-DLPFC | Percentage Change in Montgomery-Åsberg Depression Rating Scale (MADRS) Score From Pre-treatment to 1-month Post-treatment. | -11 percent change in MADRS score | Standard Deviation 29 |
Comparison: MADRS scores were assessed with generalized linear mixed models (GLMM) that used Satterthwaite approximation of degrees of freedom and robust estimation of coefficients to handle violations of model assumptions. Fixed effects of time, treatment group (sham vs. active) and their interaction were assessed.p-value: <0.001Mixed Models Analysis
Secondary
Change From Baseline Functional Connectivity to 1-month Post-treatment
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.
Time frame: Pretreatment (baseline) to 1-month post-treatment
Population: Participants with available data were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active TBS-DLPFC | Change From Baseline Functional Connectivity to 1-month Post-treatment | lsgACC_lDMN | 0.090 Z-score | Standard Deviation 0.287 |
| Active TBS-DLPFC | Change From Baseline Functional Connectivity to 1-month Post-treatment | lDMN_rDMN | -0.039 Z-score | Standard Deviation 0.702 |
| Sham TBS-DLPFC | Change From Baseline Functional Connectivity to 1-month Post-treatment | lsgACC_lDMN | -0.163 Z-score | Standard Deviation 0.258 |
| Sham TBS-DLPFC | Change From Baseline Functional Connectivity to 1-month Post-treatment | lDMN_rDMN | -0.056 Z-score | Standard Deviation 0.388 |
Comparison: Functional connectivity between lsgACC\_lDMN in participants receiving active iTBS.p-value: =0.447t-test, 2 sided
Comparison: Functional connectivity between lsgACC\_lDMN in participants receiving sham iTBS.p-value: =0.115t-test, 2 sided
Comparison: Functional connectivity between lDMN\_rDMN in participants receiving active iTBS.p-value: =0.546t-test, 2 sided
Comparison: Functional connectivity between lDMN\_rDMN in participants receiving sham iTBS.p-value: =0.607t-test, 2 sided
Secondary
Change From Baseline Functional Connectivity to Immediate Post-treatment
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.
Time frame: Pretreatment (baseline) to immediately post-treatment (day 8).
Population: Participants with available data were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active TBS-DLPFC | Change From Baseline Functional Connectivity to Immediate Post-treatment | lsgACC_lDMN | 0.071 Z-score | Standard Deviation 0.242 |
| Active TBS-DLPFC | Change From Baseline Functional Connectivity to Immediate Post-treatment | lDMN_rDMN | -0.069 Z-score | Standard Deviation 0.33 |
| Sham TBS-DLPFC | Change From Baseline Functional Connectivity to Immediate Post-treatment | lsgACC_lDMN | 0.025 Z-score | Standard Deviation 0.301 |
| Sham TBS-DLPFC | Change From Baseline Functional Connectivity to Immediate Post-treatment | lDMN_rDMN | 0.117 Z-score | Standard Deviation 0.565 |
Comparison: Functional connectivity between lsgACC\_lDMN in participants receiving active iTBS.p-value: =0.308t-test, 2 sided
Comparison: Functional connectivity between lsgACC\_lDMN in participants receiving sham iTBS.p-value: =0.778t-test, 2 sided
Comparison: Functional connectivity between lDMN\_rDMN in participants receiving active iTBS.p-value: =0.468t-test, 2 sided
Comparison: Functional connectivity between lDMN\_rDMN in participants receiving sham iTBS.p-value: =0.486t-test, 2 sided
Secondary
Change in Baseline Heart Rate Variability to 1-month Post-treatment
Heart rate variability measures will be compared pre-treatment and 1-month post-treatment.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active TBS-DLPFC | Change in Baseline Heart Rate Variability to 1-month Post-treatment | 46.609 SDNN in milliseconds | Standard Error 25.262 |
| Sham TBS-DLPFC | Change in Baseline Heart Rate Variability to 1-month Post-treatment | -26.670 SDNN in milliseconds | Standard Error 36.464 |
Comparison: We conducted a linear mixed models analysis, with a focus on the interaction term. No power analysis for this measure because number of participants was determined by other primary study aims.p-value: <0.05Mixed Models Analysis
Secondary
Change in Baseline Heart Rate Variability to Immediate Post-treatment
Heart rate variability measures will be compared pre-treatment and immediately post-treatment.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active TBS-DLPFC | Change in Baseline Heart Rate Variability to Immediate Post-treatment | 16.226 SDNN in milliseconds | Standard Error 15.245 |
| Sham TBS-DLPFC | Change in Baseline Heart Rate Variability to Immediate Post-treatment | -31.159 SDNN in milliseconds | Standard Error 35.258 |
Comparison: We used a linear mixed models analysis, with the fixed factors being treatment group and timepoint.p-value: <0.05Mixed Models Analysis
Secondary
Change in the Columbia Suicide Severity Rating Scale (C-SSRS) Score
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.
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Active TBS-DLPFC | Change in the Columbia Suicide Severity Rating Scale (C-SSRS) Score | Increased | 0 Participants |
| Active TBS-DLPFC | Change in the Columbia Suicide Severity Rating Scale (C-SSRS) Score | Decreased | 6 Participants |
| Active TBS-DLPFC | Change in the Columbia Suicide Severity Rating Scale (C-SSRS) Score | No Change | 2 Participants |
| Sham TBS-DLPFC | Change in the Columbia Suicide Severity Rating Scale (C-SSRS) Score | Decreased | 1 Participants |
| Sham TBS-DLPFC | Change in the Columbia Suicide Severity Rating Scale (C-SSRS) Score | Increased | 0 Participants |
| Sham TBS-DLPFC | Change in the Columbia Suicide Severity Rating Scale (C-SSRS) Score | No Change | 5 Participants |
Secondary
Change in the Hamilton Rating Scale for Depression (HAM-6) Score
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.
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Active TBS-DLPFC | Change in the Hamilton Rating Scale for Depression (HAM-6) Score | Decreased | 8 Participants |
| Active TBS-DLPFC | Change in the Hamilton Rating Scale for Depression (HAM-6) Score | No Change | 2 Participants |
| Active TBS-DLPFC | Change in the Hamilton Rating Scale for Depression (HAM-6) Score | Increased | 1 Participants |
| Sham TBS-DLPFC | Change in the Hamilton Rating Scale for Depression (HAM-6) Score | Decreased | 3 Participants |
| Sham TBS-DLPFC | Change in the Hamilton Rating Scale for Depression (HAM-6) Score | No Change | 6 Participants |
| Sham TBS-DLPFC | Change in the Hamilton Rating Scale for Depression (HAM-6) Score | Increased | 1 Participants |
Secondary
Percentage Change in the Hamilton Rating Scale for Depression (HAMD-17)
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.
Time frame: Pre-treatment (baseline) to immediately post-treatment (day 8).
Population: Participants who completed the protocol are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active TBS-DLPFC | Percentage Change in the Hamilton Rating Scale for Depression (HAMD-17) | -59 percent change in score | Standard Deviation 31 |
| Sham TBS-DLPFC | Percentage Change in the Hamilton Rating Scale for Depression (HAMD-17) | -20 percent change in score | Standard Deviation 22 |
Comparison: HDRS-17 scores were assessed with generalized linear mixed models (GLMM) that used Satterthwaite approximation of degrees of freedom and robust estimation of coefficients to handle violations of model assumptions. Fixed effects of time, treatment group (sham vs. active) and their interaction were assessed.p-value: =0.001Mixed Models Analysis
Secondary
Percentage Change in the Hamilton Rating Scale for Depression (HAMD-17)
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.
Time frame: pre-treatment (baseline) to 1-month post-treatment
Population: Participants who completed the protocol are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active TBS-DLPFC | Percentage Change in the Hamilton Rating Scale for Depression (HAMD-17) | -52 percent change in HAM-17 score | Standard Deviation 29 |
| Sham TBS-DLPFC | Percentage Change in the Hamilton Rating Scale for Depression (HAMD-17) | -12 percent change in HAM-17 score | Standard Deviation 27 |
Comparison: HDRS-17 scores were assessed with generalized linear mixed models (GLMM) that used Satterthwaite approximation of degrees of freedom and robust estimation of coefficients to handle violations of model assumptions. Fixed effects of time, treatment group (sham vs. active) and their interaction were assessed.p-value: =0.001Mixed Models Analysis