Individualized Neuromodulation for Anhedonic Depression

This program of research constitutes a three-arm, randomized, placebo-controlled trial testing noninvasive brain stimulation for the treatment of anhedonic depression. This trial is part of a larger, three-site study that will be conducted at UCSD, Stanford University, and Cornell University, with the overarching goals to compare competing interventions tested at each site and to combine data that will allow for the creation of an end-to-end model of anhedonic depression. By doing this, the investigators hope to gain insight and lead to the development of brain-behavior biomarkers to identify who is best suited for the different treatment options tested at each site. An additional exploratory objective is phenotyping anhedonic depression from the acquired measures.

Anhedonic patients recruited at UCSD will be randomized to one of three treatment arms to receive different forms of accelerated intermittent theta burst stimulation (aiTBS),a novel form of repetitive transcranial magnetic stimulation (rTMS) that is an FDA approved treatment for depression. These arms include: individualized accelerated iTBS (Ind-aiTBS),based on both the frequency of brain responses and electric-field (e-field) modeling of brain bioconductivity; standard accelerated iTBS (Std-aiTBS); and accelerated sham iTBS(sham). Treatment will be delivered on an accelerated schedule, over one week. Additional study sessions will occur both before and after treatment to assess for clinical, neurophysiological, and cognitive measures that will allow for both individualization of treatment and detailed assessment of the effects of the different treatment arms.

Study Overview

• Status: Recruiting
• Conditions: Anhedonia; MDD
• Intervention / Treatment: Device: Individualized Accelerated Intermittent Theta Burst Stimulation (Ind-aiTBS); Device: Standard Accelerated Intermittent Theta Burst Stimulation (Std-aiTBS); Device: Sham Accelerated Intermittent Theta Burst Stimulation (Sham)

• Study Type: Interventional
• Enrollment (Estimated): 129
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Interventional Psychiatry; Phone Number: (858) 207-0938; Email: iptrials@health.ucsd.edu

Study Locations

• United States
  • California
    • San Diego, California, United States, 92127
      • Recruiting
      • UCSD Interventional Psychiatry
      • Principal Investigator: Zafiris Daskalakis, MD, PhD
      • Contact: Interventional Psychiatry; Phone Number: 858-207-0938; Email: iptrials@health.ucsd.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or Female, between the ages of 18 and 80 at the time of screening.
• Able to read, understand, and provide written, dated informed consent prior to screening. Proficiency in English sufficient to complete questionnaires / follow instructions during fMRI assessments and aiTBS interventions. Stated willingness to comply with all study procedures, including availability for the duration of the study, and to communicate with study personnel about adverse events and other clinically important information.
• Currently diagnosed with Major Depressive Disorder (MDD) or Bipolar Disorder type II and meets criteria for a Major Depressive Episode, according to the criteria defined in the Diagnosis and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5).
• Medical records confirming a history of moderate to severe treatment-resistance as defined an Antidepressant Treatment History Form (ATHF) score for that antidepressant trial of > 3 in the current episode OR have been unable to tolerate at least 2 separate trials of antidepressants of inadequate dose and duration (ATHF score of 1 or 2 on those 2 separate antidepressants) OR have a combination of one failed trial and one not tolerated trial, per the definitions above.
• MADRS score of ≥20 at screening (Visit 1).
• Access to ongoing psychiatric care before and after completion of the study.
• Access to open label neuromodulation treatment after study completion.
• Must be on a stable antidepressant therapeutic regimen for 6 weeks prior to study enrollment and agree to continue this regimen throughout the study period.
• In good general health, as evidenced by medical history.
• For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation.
• Agreement to adhere to Lifestyle Considerations throughout study duration.

Exclusion Criteria:

• Pregnancy
• History of or current psychotic disorder or depression with psychotic features
• Severe borderline personality disorder.
• Diagnosis of Intellectual Disability or Autism Spectrum Disorder
• Current moderate or severe substance use disorder or demonstrating signs of acute substance withdrawal
• Urine screening test positive for illicit substances
• Clinically significant suicidal ideation with plan
• Any history of ECT (greater than 8 sessions) without a clinical meaningful response.
• Recent (during the current depressive episode) or concurrent use of rapid acting antidepressant agent (i.e., ketamine or a course of ECT) in the last 30 days
• History of significant neurologic disease, including dementia, Parkinson's or Huntington's disease, brain tumor, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma
• Untreated or insufficiently treated endocrine disorder.
• Contraindication to receiving rTMS (e.g., metal in head, history of seizure, known brain lesion)
• Contraindication to MRI (ferromagnetic metal in their body)
• Treatment with an investigational drug or other intervention within the study period
• Unstable symptoms between screening and baseline as defined by a ≥ 30% change in MADRS score.
• Require a benzodiazepine with a dose > lorazepam 2 mg/day or equivalent or any anticonvulsant.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Individualized Accelerated Intermittent Theta Burst Stimulation (Ind-aiTBS); Patients will receive individualized unilateral accelerated theta-burst stimulation to the left dorsal lateral prefrontal cortex for 5 consecutive days, with a total of 10 hours a day. Treatment will be 10min with 50min of breaks in between the 10 sessions. The target for stimulation will be individualized using the participant's fMRI scans by finding the region of the DLPFC most anti-correlated with the subgenual anterior cingulate cortex (sgACC). This target will be determined using e-field modeling and theta-gamma coupling.	Device: Individualized Accelerated Intermittent Theta Burst Stimulation (Ind-aiTBS); active side magnetic coil stimulation applied to individualized target in the left dorsal lateral prefrontal cortex.; Other Names: MagStim Cool B65- A/P
Active Comparator: Standard Accelerated Intermittent Theta Burst Stimulation (Std-aiTBS); Patients will receive unilateral accelerated theta-burst stimulation to the left dorsal lateral prefrontal cortex for 5 consecutive days, with a total of 10 hours a day. Treatment will be 10min with 50min of breaks in between the 10 sessions.	Device: Standard Accelerated Intermittent Theta Burst Stimulation (Std-aiTBS); active side magnetic coil stimulation applied to standardized target in the left dorsal lateral prefrontal cortex.; Other Names: MagStim Cool B65- A/P
Sham Comparator: Sham Accelerated Intermittent Theta Burst Stimulation (sham); Patients will receive sham unilateral accelerated theta-burst stimulation to the left dorsal lateral prefrontal cortex for 5 consecutive days, with a total of 10 hours a day. Treatment will be 10min with 50min of breaks in between the 10 sessions.	Device: Sham Accelerated Intermittent Theta Burst Stimulation (Sham); sham side magnetic coil stimulation applied to the left dorsal lateral prefrontal cortex.; Other Names: MagStim Cool B65- A/P

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in MADRS Scores	To evaluate the effects of individualized accelerated iTBS (using BOTH the frequency and e-field individualization; Ind-aiTBS) compared to standard accelerated iTBS (Std-aiTBS) and sham accelerated iTBS (sham) on depression severity measured with the Montgomery- Asbery Depression Rating Scale (MADRS).	8 weeks
Change in DARS Scores	To evaluate the effects of individualized accelerated iTBS (using BOTH the frequency and e-field individualization; Ind-aiTBS) compared to standard accelerated iTBS (Std-aiTBS) and sham accelerated iTBS (sham) on anhedonia as measured with the Dimensional Anhedonia Rating Scale (DARS).	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of Neuroplasticity	Analysis of transcranial magnetic stimulation concurrent with electroencephalogram (TMS-EEG) to extract activation of the left dorsolateral prefrontal cortex (DLPFC). Changes in activation between pre- and post-neurophysiology measures will be compared between the three treatment arms to determine the effects of Ind-aiTBS on neuroplasticity as compared to Std-aiTBS and sham.	8 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Predictive TMS-EEG Biomarker	Determine if baseline TMS-EEG predicts changes in anhedonia symptoms, as measured through correlation with changes in the MADRS and DARS from pre- to post-treatment.	8 weeks
Predictive fMRI Biomarker	Determine if baseline fMRI predicts changes in anhedonia symptoms, as measured through correlation with changes in the MADRS and DARS from pre- to post-treatment.	8 weeks
Cross-Sectional TMS-EEG Biomarker	Test for cross-sectional differences in TMS-EEG as a function of anhedonia symptoms measured by the MADRS and DARS at pre-treatment.	8 weeks
Cross-Sectional fMRI Biomarker	Test for cross-sectional differences in fMRI as a function of anhedonia symptoms measured by the MADRS and DARS at pre-treatment.	8 weeks

Collaborators and Investigators

• Sponsor: University of California, San Diego
• Collaborators: Stanford University; Cornell University; Wellcome Leap Organization

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2022
• Primary Completion (Estimated): July 1, 2024
• Study Completion (Estimated): July 1, 2024

Study Registration Dates

• First Submitted: August 4, 2022
• First Submitted That Met QC Criteria: September 11, 2022
• First Posted (Actual): September 13, 2022

Study Record Updates

• Last Update Posted (Estimated): November 9, 2023
• Last Update Submitted That Met QC Criteria: November 6, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Anhedonia
• Other Study ID Numbers: 221649-2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes