Major Depressive Disorder
Conditions
Brief summary
Major Depressive Disorder (MDD) has a high prevalence, is the leading cause of disability, and currently available interventions are associated with side effects and high treatment resistance. There is an urgent need for the development of novel interventions for MDD with alternate mechanisms of action. Temporal Interference (TI) stimulation is a newly emerging form of transcranial alternating current stimulation (tACS) that involves the application of two high-frequency currents at slightly different kHz frequencies. Since neurons, due to their intrinsic low-pass filtering, do not respond to high frequencies (i.e. \> 100 Hz), TI relies on the 'beat' interaction leading to neuromodulation at any given location, resulting in a much smaller focus and allowing for better targeting. The subgenual cingulate cortex (SCC) appears to be critical in the pathophysiology of depression and treatment response, especially in treatment-resistant cases. Non-invasive treatments, however, are not able to accurately target SCC due to its deep location within the brain. In this trial, 30 participants meeting the diagnostic criteria for MDD will be randomized to receive 10 sessions of 130 Hz TI delivered daily for 30 minutes, or 10 sessions of sham stimulation. During the stimulation, participants will be watching emotional film clips to enhance target engagement. The investigators will collect metrics of SCC target engagement using the resting-state fMRI and EEG technologies, and determine feasibility, tolerability, safety, and therapeutic efficacy of TI stimulation in MDD. The results of this trial will inform the TI technology as a therapeutic tool for network-based psychiatric disorders, including MDD, and be vital for the design and development of a large-scale randomized-controlled trial.
Interventions
DEVICETemporal Interference stimulation
TI involves simultaneous delivery of independent currents to the brain at slightly different kHz frequencies, which are individually too high to recruit neural firing. However, the difference ('beat') frequency where the currents overlap (i.e., temporally interfered) is low enough to drive neural activity. The interferometrically derived low frequencies have been demonstrated to activate neurons at a selected focus without activation of surrounding regions in awake mice. The safety of the TI paradigm has been demonstrated in over 60 healthy human volunteers, and finite element modeling of simulations of TI fields in human anatomical models suggests that large subcortical structures such as the hippocampus or SCC could be selectively targeted. However, the precise TI parameters for selective engagement of SCC in healthy participants and in MDD is currently unknown.
DEVICESham stimulation
Electrodes will be placed in the same location on the head as that for the TI intervention; 0 mA of electrical current will be delivered to the brain (compared to 2 mA in the active intervention arm), therefore it is expected to elicit no changes in neural activity.
Sponsors
Beth Israel Deaconess Medical Center
Northeastern University
Centre for Addiction and Mental Health
Charite University, Berlin, Germany
Toronto Metropolitan University
Unity Health Toronto
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The following roles will be blinded: i) Investigators and care providers; ii) Enrolled participants; iii) Outcome assessors; iv) MRI technician
Intervention model description
This is a pilot, sham-controlled, quadruple-blind clinical trial to demonstrate target engagement of SCC with TI, as well as assess feasibility, safety, tolerability, and preliminary therapeutic efficacy of TI stimulation in patients with MDD.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
- Patients will be included if they: 1. provide written informed consent before initiation of any study-related procedures 2. are outpatients 3. meet the DSM-5 criteria for major depressive disorder (MDD) with a current major depressive episode (MDE) without psychotic features as confirmed at Screening by the Mini International Neuropsychiatric Interview (MINI) 4. are male or female, 18 to 65 years of age (inclusive) at screening 5. have a Montgomery-Åsberg Depression Rating Scale (MADRS) total score of ≥ 20 (moderate to severe depression) at screening 6. have had no increase or initiation of any psychotropic medication in the 4 weeks prior to screening 7. able to adhere to the treatment schedule 8. pass the TI adult safety screening questionnaire 9. are able to understand and comply with the requirements of the study, as judged by the investigator(s)
Exclusion criteria
- Patients will be excluded if they: 1. have an acute alcohol or substance use disorder, withdrawal symptoms requiring detoxification, or went through detoxification treatment (inpatient or outpatient) within 3 months before Screening, as obtained from MINI, Module I (Alcohol Use Disorder) and Module J (Substance Use Disorder, Non-Alcohol) assessed at Screening 2. have a concomitant major unstable medical illness, active hepatitis B virus (HBV), hepatitis C virus (HPC), human immunodeficiency virus (HIV), active COVID-19 infection, cardiac pacemaker or implanted medication pump, as per medical history provided by the participant 3. have active suicidal intent, confirmed by a 'Yes' response to Question B3 AND either Question B10 or B11, obtained from the MINI Suicidality, Module B (Suicidality), OR confirmed by the MADRS item #10 score ≥ 4, both assessed at Screening 4. have a current clinical diagnosis of autism, dementia, or intellectual disability 5. take medications prohibited by the protocol. Medications will be reviewed by the responsible MD 6. are pregnant or lactating 7. have any prior or current diagnosis of bipolar I or II disorder, MDD with psychotic features, schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, or current psychotic symptoms as obtained from MINI, Module C (Manic and Hypomanic Episodes) and Module K (Psychotic Disorders and Mood Disorders with Psychotic Features) assessed at Screening 8. have any prior or current diagnosis of obsessive-compulsive disorder, post-traumatic stress disorder (current or within the last year), confirmed by MINI and assessed by a study investigator to be primary and causing greater impairment than MDD 9. have a diagnosis of any personality disorder, and assessed by a study investigator to be primary and causing greater impairment than MDD 10. have received TI for any previous indication due to the potential compromise of subject blinding 11. have any significant neurological disorder or insult including, but not limited to: any condition likely to be associated with increased intracranial pressure, space-occupying brain lesion, any history of seizure except those therapeutically induced by ECT or a febrile seizure of infancy, cerebral aneurysm, Parkinson's disease, Huntington's chorea, multiple sclerosis, significant head trauma with loss of consciousness for greater than 5 minutes, current history of poorly controlled migraines including chronic medication for migraine prevention 12. have an intracranial implant (e.g., aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) or any other metal object within or near the head, excluding the mouth, that cannot be safely removed 13. if participating in psychotherapy, have NOT been in stable treatment for at least 3 months prior to entry into the study or anticipate change in the frequency of therapeutic sessions or therapeutic focus over the duration of the study 14. have a clinically significant laboratory abnormality, in the opinion of one of the principal investigators or study physicians 15. currently take medications that potentially limit the TI efficacy 16. have a non-correctable clinically significant sensory impairment (i.e., cannot hear well enough to cooperate with an interview) 17. have a clinical finding that is unstable or that, in the opinion of the investigator(s), would be negatively affected by the study medication or that would affect the study medication (e.g., diabetes mellitus, hypertension, unstable angina) 18. have uncorrected hypothyroidism or hyperthyroidism. Subjects needing a thyroid hormone supplement to treat hypothyroidism will be excluded if they have NOT been on a stable dose of the medication for 30 days prior to enrolment 19. have any other condition that, in the opinion of the investigator(s), would adversely affect the subject's ability to complete the study or its measure 20. wear a hairstyle or headdress at the time of the stimulation that prevents electrode contact with the scalp or would interfere with the stimulation (e.g., thick or curly hair) 21. have any contraindications for receiving TI or undergoing MRI scans (e.g., hip circumference \>180 cm or metal in the body)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Neuroimaging - Signal variance | End of 2nd week of intervention | Signal variance within SCC to demonstrate SCC target engagement to TI stimulation |
| Neuroimaging - Functional connectivity | End of 2nd week of intervention | Seed-based resting-state functional connectivity of SCC to demonstrate SCC target engagement to TI stimulation |
| Neuroimaging - Anatomical connectivity | End of 2nd week of intervention | Anatomical connectivity of SCC to demonstrate SCC target engagement to TI stimulation |
| Neuroimaging - Perfusion metrics | End of 2nd week of intervention | Cerebral blood flow within SCC to demonstrate SCC target engagement to TI stimulation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Correlation between EEG and depression symptoms | Baseline, end of 1st week of intervention, and end of 2nd week of intervention | Correlation between changes in features of gamma or theta oscillations (EEG) and changes in depression symptoms measured by the HAM-D |
| EEG Signals - MMN event-related potential | Baseline, end of 1st week of intervention, and end of 2nd week of intervention | Changes in mismatch negativity (MMN) event-related potential amplitude and latency |
| Tolerability - Adverse events | End of 1st week of intervention, end of 2nd week of intervention, 1 week post-intervention, and 4 weeks post-intervention | Incidence of treatment-emergent adverse events |
| Clinical change in depression symptoms | Baseline, end of 1st week of intervention, end of 2nd week of intervention, 1 week post-intervention, and 4 weeks post-intervention | Change in symptoms of depression measured by the 17-item Hamilton Depression Rating Scale (HAM-D); scores range from 0 to 53, and higher scores indicate more severe depression symptoms. |
| Trial Feasibility - Recruitment rate | Enrollment | The number of participants enrolled into the study per month |
| Trial Feasibility - Intervention adherence | End of 2nd week of intervention | Percentage of participants who completed ≥80% of scheduled intervention sessions |
| Trial Feasibility - Dropout rate | End of 1st week of intervention, end of 2nd week of intervention, 1 week post-intervention, and 4 weeks post-intervention | The proportion of participants who discontinue participation in the study before completion |
| EEG Signals - Time domain features | Baseline, end of 1st week of intervention, and end of 2nd week of intervention | Changes in time domain features of gamma oscillation on resting-state EEG Changes in time domain features of theta oscillation on resting-state EEG |
| EEG Signals - Frequency domain features | Baseline, end of 1st week of intervention, and end of 2nd week of intervention | Changes in frequency domain features of gamma oscillation on resting-state EEG Changes in frequency domain features of theta oscillation on resting-state EEG |
| EEG Signals - Functional connectivity | Baseline, end of 1st week of intervention, and end of 2nd week of intervention | Changes in functional connectivity on resting-state EEG |
Countries
Canada
Contacts
Primary ContactVenkat Bhat, MD MSc
Backup ContactIlya Demchenko, MSc
Outcome results
None listed