The central goal of this application is to demonstrate the causal contribution of reward learning signals (expected values and reward prediction errors \[RPE\]) to antidepressant responses (Aim1) by experimentally manipulating expected values using transcranial magnetic stimulation (TMS) targeting the vmPFC (Aim 2) and μ-opioid striatal RPE signal using pharmacological approaches (Aim 3).
The central goal of this study is to demonstrate the causal contribution of reward learning signals (expected values and RPEs) to antidepressant responses (Aim1) by experimentally manipulating expected values using transcranial magnetic stimulation (TMS) targeting the vmPFC (Aim 2) and μ-opioid striatal RPE signal using pharmacological approaches (Aim 3). In a 3x3 factorial double-blind trial, the investigators will randomize 120 unmedicated major depressive disorder (MDD) adults (18-55 years) to one of three between-subject opioid conditions: the μ-opioid agonist buprenorphine (n=40), the μ-opioid antagonist naltrexone (n=40), or the inert pill (n=40). Within each arm, individuals will be assigned to receive three within-subject counterbalanced sessions of TMS targeting the vmPFC-intermittent TBS (iTBS) expected to potentiate the vmPFC, continuous TBS (cTBS) expected to de-potentiate the vmPFC, and sham TBS (sTBS). These experimental manipulations will be used to modulate trial-by-trial reward learning signals and related brain activity during the Antidepressant fMRI Task. Understanding the mechanisms underlying antidepressant responses is essential to identify novel therapeutic targets for depression.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
DOUBLE
Enrollment
120
Buprenorphine is a μ-opioid partial agonist and kappa-opioid antagonist that is used to treat moderate to severe pain and opioid dependence. The intramuscular administered opioid agonist which will be used to modulate reward learning signals to understand placebo effects in patients with depression. In the buprenorphine condition, participants will receive one IM injection of 0.3mg/1ML buprenorphine hydrochloride (Buprenex®. Richmond, VA: Reckitt Benckiser Pharmaceuticals Inc.; 2006) (onset of action: ≥15 minutes; peak effect: \~1 hour; duration: \~6 hours) and an oral placebo tablet.
Naltrexone is thought to strongly block μ-opioid receptors. Oral (pill) opioid antagonist which will be used to modulate reward learning signals to understand placebo effects in participants with depression. In the naltrexone condition, participants will receive one tablet of 50mg Naltrexone hydrochloride (ReVia®. Toronto, ON: Teva Canada Limited; 2015) (onset of action: ≥15 minutes; peak effect: \~1 hour; duration: \~24 hours) and a saline IM injection.
Bellefield Tower
Pittsburgh, Pennsylvania, United States
BOLD Responses in the vmPFC-VS circuit
Changes in blood oxygenation level-dependent (BOLD) signal during the Antidepressant fMRI Task.
Time frame: Approximately at day 7, 14, 21.
TBS Effects of BOLD Response
Changes in BOLD signal during the Antidepressant fMRI Task between iTBS vs. sTBS, and cTBS vs. sTBS.
Time frame: Approximately at day 7, 14, 21.
Opioid Modulation Effects on BOLD Responses in the vmPFC-VS circuit
Changes in BOLD signal during the Antidepressant fMRI Task between Buprenorphine vs. inert pill, and Naltrexone vs. inert pill.
Time frame: Approximately at day 7, 14, 21.
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Oral placebo: to match the oral naltrexone.
IM saline placebo: to match the i.v. buprenorphine.
Participants will receive two blocks of each TBS form. During the first block, stimulation intensity will be gradually escalated in 5% increments (from 80% to 110% rMT) in order to enhance tolerability. In all conditions, the investigators will apply 600 pulses of theta burst at 110% RMT. Each block of iTBS will consist of 20 trains, each lasting 2s with intertrain intervals of 8s, for a total of 192s. Each block of cTBS will consist of one continuous train of 40s. The sTBS will make use of two surface electrodes placed on the scalp.