Concurrent fMRI-guided rTMS and Cognitive Therapy for the Treatment of Major Depressive Episodes

Major Depressive Disorder Clinical Trial

Official title: Concurrent fMRI-guided rTMS and Cognitive Therapy for the Treatment of Major Depressive Episodes

Status Recruiting

Clinical Trial Summary

Background:

Repetitive transcranial magnetic stimulation (rTMS) is a treatment for depression. It stimulates the brain. Researchers want to see if using magnetic resonance imaging (MRI) scans helps locate the best area for rTMS in each person. They also want to find other ways to make it more effective.

Objective:

To study the effects of combining MRI- guided transcranial magnetic stimulation (TMS) and talk therapy on the brain in people with depression.

Eligibility:

Adults ages 18-75 with a major depressive disorder and current depression. If taking an antidepressant, should have been doing so for at least 4 weeks.

Design:

Participants will be screened with medical and psychiatric history, psychiatric evaluation, physical exam, and blood and urine tests.

Phase 1 is 1-4 visits in 1 week. Participants will have:

• Brain MRI. Participants will lie on a table in a scanner.

• Questions about their medical history and psychology symptoms

• Tests of mood and thinking

• Tests of brain activity. Participants may do tasks during these tests:

• A cone with magnetic detectors is put on the head.

• A cap with electrodes is put on the scalp.

• TMS. A brief electrical current passes through a wire coil on the scalp.

• A metal disk will be placed on the arm. A nerve will be stimulated with a small electrical shock.

Phase 2 is about 6 to 7 weeks.

• There will be 30 daily sessions of combined therapy and repetitive TMS (rTMS) for 6 weeks.

• Participants will receive rTMS and another therapy by computer.

• For rTMS, repeated pulses will pass through the coil.

• This is followed by up to 3 additional visits, when:

• Participants will repeat Phase 1 tests

• Participants will rate their depression symptoms.

Phase 3 is 3 visits over 3 months. Participants will rate their depression symptoms and repeat some of the previous questionnaires and tests of mood and thinking.

Clinical Trial Description

Objective

Despite the growing use of repetitive transcranial magnetic stimulation (rTMS) as a treatment for unipolar major depression, its typical effect sizes have been modest, and both methodological and conceptual challenges remain regarding how to optimize its efficacy. Two key elements have been missing from current work: first, to take an RDoC approach and link the treatment to a comprehensive model of the neurocircuitry underlying depression, where applying such a model to personalize the site of stimulation is likely to significantly improve the efficacy of rTMS; and second, to maximize neural changes to the engaged depression network by utilizing cognitive paired associate stimulation (C-PAS), a technique we have developed over the last decade in which noninvasive stimulation is applied to the targeted region while the circuit is engaged in processing related to desired behavior (here, through the simultaneous use of cognitive behavioral therapy). The concurrent firing in the emotional regulation circuit caused by TMS pulses and by the CBT will lead to neural plasticity according to the Hebbian conception of fire together, wire together, while repeated stimulation over the course of multiple TMS sessions will induce neuroplasticity to accelerate and strengthen those changes, which are expected to be therapeutic. We thus intend to test a novel integrative multimodal treatment for MDD consisting of a theory-based protocol for individualized optimization of rTMS site of stimulation plus concurrent behavioral interventions targeting the same dysfunctional neural circuitry. Our targeting procedure is based on recent developments in the psychology and neurobiology of self-regulation which offer a promising conceptual framework for identifying neural network mechanisms of action in rTMS for depression, as well as for developing guidelines for individualized rTMS treatment. As preliminary data, we report initial feasibility data from a clinical paradigm in which five adults with major depressionreceived TMS to the left middle frontal gyrus targeted on an individual basis using fMRI, while simultaneously receiving a previously validated self-regulation-based psychotherapy. Here, we will test this individualized method in a larger randomized trial.

Study Population

The study population will consist of 50 individuals between the 18 and 65 years of age, with a diagnosis of treatment-resistant Major Depressive Disorder (MDD).

Study Design

This single site study is a proof-of-concept clinical trial to test both functional states associated with an antidepressant response to a six week course of C-PAS using concomitant SST and 10 Hz rTMS neuronavigated to left DLPFC, as well as the feasibility and safety of such a course for long-term improvement in depressive symptoms. The proposed study will be conducted over 3 phases. Phase I will consist of screening, consent, and baseline measures. Screening will occur under the ETPB screening protocol (01-M-0254). Phase II will consist of a 6-week double-blind sham controlled trial of neuronavigated TMS cognitive therapy. Participants will be randomized to two groups, receiving either Active or Sham fMRI-guided-TMS, while involved in a cognitive therapy session. Subjects will participate in 30 daily sessions over 6 weeks, with MRI sessions both prior to and immediately after the course of TMS. Additionally, MEG may optionally be performed at baseline, immediately after the first TMS/SST session, and immediately after the entire course of TMS, and an optional battery of TMS/EEG excitability and plasticity measures may be performed pre- and post-TMS/SST course. In Phase III, the study team will provide standard of care for depression for up to three months, and will prescribe a relapse prevention strategy, in consultation with the referring physician, including TMS (which is consistent with standard of care).

Outcome Measures

Primary outcome measures are change in magnitude of BOLD signal recorded in pre- and post-TMS course MRI sessions, in the DLPFC region targeted with TMS based on individual activations in that region found at baseline using the priming task, and pre- and post-TMS course connectivity changes between DLPFC (measured with DTI and resting state functional connectivity), and other regions associated with the emotional regulation network, specifically OFC, medial PFC, precuneus, and ACC. Pre and post TMS course change in depression severity scores (HDRS, MADRS) will also be found, in order to look for correlations with these MRI measures. Secondary outcome measures will be ratings from the BSL, C-SSRS, CTQ, HAM-A, NIH-BFI, PANAS, RBANS, RRS, SHAPS, and TLEQ, as well as electrophysiological changes using MEG and EEG measures. ;

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Major
• Major Depressive Disorder

• NCT number: NCT03289923
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Ekaete C Ekpo
• Phone: (301) 827-1874
• Email: ekaete.ekpo@nih.gov
• Status: Recruiting
• Phase: N/A
• Start date: May 17, 2018
• Completion date: March 1, 2029