Depressions, Refractory, Epilepsy
Conditions
Keywords
epilepsy, depression, refractory, TMS
Brief summary
The purpose of this study is to determine if low-frequency transcranial magnetic stimulation (TMS) is safe and feasible for treating depressive symptoms in patients with epilepsy. Patients will receive an accelerated protocol of TMS consisting of three consecutive days of treatment. Patients will have in-person follow up visits after one month and again after six months.
Detailed description
This is a pilot study designed primarily to assess whether patients with epilepsy can safely tolerate low-frequency transcranial magnetic stimulation in an accelerated protocol to treat depression. The investigators aim to treat 12 patients with epilepsy and comorbid depression to receive a total of 15 hours of transcranial magnetic stimulation over 3 days at Dartmouth-Hitchcock Medical Center (DHMC). The investigators will assess safety of this protocol with regards to seizure frequency and other side effects of TMS treatment and the feasibility of using an accelerated protocol in this patient population. In addition to these primary aims, our secondary goal is to determine if dense array EEG can provide a useful biomarker for depression and its treatment in focal epilepsy. A structural and functional MRI will be obtained before treatment and a dense array EEG before and after TMS treatment to assess for changes in specific dense array EEG based biomarkers. In addition to recruiting patients, the study staff will likewise request that family members or friends of the patient accompany the patient monitor him/her for increased seizure frequency. The recruited family member will bring the patient to the treatment and stay with the patient overnight at a local hotel and monitor for possible seizures or other adverse events of treatment. Family members will be instructed in seizure safety and be given emergency phone numbers to call if the patient is experiencing adverse effects of TMS.
Interventions
DEVICETranscranial Magnetic Stimulation
Repetitive transcranial magnetic stimulation (TMS) is a focal, nonpharmacological, noninvasive method for stimulating the brain and modulating neural network activity. To administer TMS, an electromagnetic coil is placed on the scalp, and uses electrical current to create magnetic fields that depolarize or hyperpolarize neurons in the brain.
Sponsors
The Diamond Foundation Inc.
Dartmouth-Hitchcock Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Age 18 or older * Able and willing to provide informed consent. * Diagnosis of epilepsy confirmed by the study neurologist (KB). * English-speaking * Not pregnant * Able to safely undergo MRI (as assessed by MRI safety form). * Have a family member or friend (proxy) who will be able to bring the patient to the hospital and serve as a safety monitor during stay in study hotel for two consecutive nights. * Patients on stable doses of current antiepileptic and antidepressant medications for 1 month.
Exclusion criteria
* Significant cognitive impairment measured by the Montreal Cognitive Assessment (MOCA) \<23. * History of other major psychiatric disorders (e.g., schizophrenia, bipolar disorder, substance use disorder (except caffeine and nicotine) or presence of unstable medical comorbidities. * Actively/imminently suicidal (QIDS item 12 score \> 2 or Mini-International Neuropsychiatric Interview (MINI) Suicidality module score \> 16) * Greater than 10 seizures per week during 1 month prior. * History of stroke, moderate-severe traumatic brain injury or other major neurological disorder. * Any magnetic or implanted device that will interfere with ability to safely receive MRI and/or TMS treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Seizure Frequency Expressed as the Average Number of Seizures Experienced by All Participants and Recorded at Specified Time Points Throughout the Study. | Baseline, 1-week post-treatment, 1-month post-treatment, 6-month post-treatment follow-up | The hypothesis is that TMS treatment will not produce serious adverse events defined as an increase in the average number of seizures across all participants. This data is collected from the time of enrollment, and then at baseline, 1-week post treatment, 1-month post-treatment, and 6-month post treatment. The seizures are reported directly by the participants during check-ins with the research staff at the study specified study timepoints. |
| Percentage of Participants Who Complete the TMS Treatment | 15 one-hour sessions of TMS over 3 days | The percentage of participants who completed the TMS treatment as measured by the total number of participants (expressed as percentage) who completed 15-hour sessions of TMS over 3 days. |
| Number of Treatment-emergent Adverse Events as Measured by a Modified Systematic Assessment for Treatment Emergent Events (SAFTEE). | Day 1, 2, and 3 of TMS treatment | The hypothesis is that TMS treatment will not be associated with a higher rate of adverse events as measured by a modified Systematic Assessment for Treatment Emergent Events (SAFTEE) given pre-TMS treatment and immediately post-TMS sessions. SAFTEE is a tool used to assess participants' adverse events and is presented to all participants before and right after each TMS session. The outcome is expressed as a total number of adverse events across all participants and all TMS treatment sessions. |
| Measuring Biomarker for Depression Using Dense-array EEG | Baseline, Post-TMS, 1-month and 6-month follow-up | Examine the utility of dense-array electroencephalogram (EEG) as a biological marker (biomarker) of depression and response to treatment with low-frequency transcranial magnetic stimulation (TMS) in patients with Epilepsy. The ratio of alpha power between the right and the left hemispheres is considered an EEG based biomarker for depression. It is obtained by dividing alpha power from the right brain hemisphere divided by alpha power measured from the left brain hemisphere. A ratio higher than 1 (1 infers that both sides of the brain are equal) correlates with depression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Depression Severity Related to the Study Interventions. | 1-week post-treatment, 1-month post-treatment, 3-month post-treatment, and 6-month post-treatment follow-up | Exploratory analyses will investigate changes in depression scores as a result of the study protocol and interventions. Quick Inventory of Depressive Symptomology (QIDS) is a self-assessment questionnaire used in this study to measure participants' depression symptoms. For Major Depressive Disorder scores of 0-5 indicate no depression, 6-10 indicates mild depression, 11-15 is moderate depression, 16-20 is severe depression, and 21-27 is very severe depression. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Low Frequency TMS Intervention Patients will receive low-frequency TMS on an accelerated schedule over three consecutive days.
Transcranial Magnetic Stimulation: Repetitive transcranial magnetic stimulation (TMS) is a focal, nonpharmacological, noninvasive method for stimulating the brain and modulating neural network activity. To administer TMS, an electromagnetic coil is placed on the scalp, and uses electrical current to create magnetic fields that depolarize or hyperpolarize neurons in the brain. | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 4 |
| Overall Study | screen fail | 3 |
Baseline characteristics
| Characteristic | Low Frequency TMS Intervention |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 12 Participants |
| Region of Enrollment United States | 12 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 12 |
| other Total, other adverse events | 12 / 12 |
| serious Total, serious adverse events | 0 / 12 |
Outcome results
Primary
Change in Seizure Frequency Expressed as the Average Number of Seizures Experienced by All Participants and Recorded at Specified Time Points Throughout the Study.
The hypothesis is that TMS treatment will not produce serious adverse events defined as an increase in the average number of seizures across all participants. This data is collected from the time of enrollment, and then at baseline, 1-week post treatment, 1-month post-treatment, and 6-month post treatment. The seizures are reported directly by the participants during check-ins with the research staff at the study specified study timepoints.
Time frame: Baseline, 1-week post-treatment, 1-month post-treatment, 6-month post-treatment follow-up
Population: Subjects 3 and14 were lost to 6-month follow-up for unknown reasons. Subjects 9 and 13 were lost to 6-month follow-up due to COVID 19.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Low Frequency TMS Intervention | Change in Seizure Frequency Expressed as the Average Number of Seizures Experienced by All Participants and Recorded at Specified Time Points Throughout the Study. | Baseline | 5.83 average number of seizures |
| Low Frequency TMS Intervention | Change in Seizure Frequency Expressed as the Average Number of Seizures Experienced by All Participants and Recorded at Specified Time Points Throughout the Study. | 1-week post-treatment | 0 average number of seizures |
| Low Frequency TMS Intervention | Change in Seizure Frequency Expressed as the Average Number of Seizures Experienced by All Participants and Recorded at Specified Time Points Throughout the Study. | 1-month post-treatment | 1.42 average number of seizures |
| Low Frequency TMS Intervention | Change in Seizure Frequency Expressed as the Average Number of Seizures Experienced by All Participants and Recorded at Specified Time Points Throughout the Study. | 6-month post-treatment | 1.0 average number of seizures |
Primary
Measuring Biomarker for Depression Using Dense-array EEG
Examine the utility of dense-array electroencephalogram (EEG) as a biological marker (biomarker) of depression and response to treatment with low-frequency transcranial magnetic stimulation (TMS) in patients with Epilepsy. The ratio of alpha power between the right and the left hemispheres is considered an EEG based biomarker for depression. It is obtained by dividing alpha power from the right brain hemisphere divided by alpha power measured from the left brain hemisphere. A ratio higher than 1 (1 infers that both sides of the brain are equal) correlates with depression.
Time frame: Baseline, Post-TMS, 1-month and 6-month follow-up
Population: Subject 1: post-TMS HD-EEG data file is not retrievable. Subject 3 and 4: baseline and post-TMS data were too noisy for analysis in frequency domain, and therefore, were excluded from the following analysis.~6-month follow-up: was not collected for this outcome measure due to COVID-19 pandemic
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low Frequency TMS Intervention | Measuring Biomarker for Depression Using Dense-array EEG | Baseline alpha power asymmetry | 1.29 frontal alpha power ratio R/L | Standard Deviation 0.88 |
| Low Frequency TMS Intervention | Measuring Biomarker for Depression Using Dense-array EEG | Post-TMS alpha power asymmetry | 1.10 frontal alpha power ratio R/L | Standard Deviation 0.21 |
| Low Frequency TMS Intervention | Measuring Biomarker for Depression Using Dense-array EEG | 1-Month Follow-up alpha power asymmetry | 1.35 frontal alpha power ratio R/L | Standard Deviation 0.53 |
Primary
Number of Treatment-emergent Adverse Events as Measured by a Modified Systematic Assessment for Treatment Emergent Events (SAFTEE).
The hypothesis is that TMS treatment will not be associated with a higher rate of adverse events as measured by a modified Systematic Assessment for Treatment Emergent Events (SAFTEE) given pre-TMS treatment and immediately post-TMS sessions. SAFTEE is a tool used to assess participants' adverse events and is presented to all participants before and right after each TMS session. The outcome is expressed as a total number of adverse events across all participants and all TMS treatment sessions.
Time frame: Day 1, 2, and 3 of TMS treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Frequency TMS Intervention | Number of Treatment-emergent Adverse Events as Measured by a Modified Systematic Assessment for Treatment Emergent Events (SAFTEE). | 1 adverse events |
Primary
Percentage of Participants Who Complete the TMS Treatment
The percentage of participants who completed the TMS treatment as measured by the total number of participants (expressed as percentage) who completed 15-hour sessions of TMS over 3 days.
Time frame: 15 one-hour sessions of TMS over 3 days
Population: Participants who started the TMS treatment and completed all sessions
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Frequency TMS Intervention | Percentage of Participants Who Complete the TMS Treatment | 12 Participants |
Secondary
Changes in Depression Severity Related to the Study Interventions.
Exploratory analyses will investigate changes in depression scores as a result of the study protocol and interventions. Quick Inventory of Depressive Symptomology (QIDS) is a self-assessment questionnaire used in this study to measure participants' depression symptoms. For Major Depressive Disorder scores of 0-5 indicate no depression, 6-10 indicates mild depression, 11-15 is moderate depression, 16-20 is severe depression, and 21-27 is very severe depression.
Time frame: 1-week post-treatment, 1-month post-treatment, 3-month post-treatment, and 6-month post-treatment follow-up
Population: 3-month follow-up: subjects 1 \& 2: data not available as this was not in the protocol at the time 6-month follow-up: subjects 3, 9, 13, 14: lost to follow-up, no data available for analysis
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Low Frequency TMS Intervention | Changes in Depression Severity Related to the Study Interventions. | Screening Visit | 16.9 score on a scale |
| Low Frequency TMS Intervention | Changes in Depression Severity Related to the Study Interventions. | 1-week post treatment | 8.2 score on a scale |
| Low Frequency TMS Intervention | Changes in Depression Severity Related to the Study Interventions. | 1-month post treatment | 8.7 score on a scale |
| Low Frequency TMS Intervention | Changes in Depression Severity Related to the Study Interventions. | 3-month post-treatment | 8.8 score on a scale |
| Low Frequency TMS Intervention | Changes in Depression Severity Related to the Study Interventions. | 6-month post-treatment | 9.6 score on a scale |