Rapid Antidepressant Improvement Secondary to Excitatory Brain Responses

Summary

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).

Conditions

• Major Depressive Disorder
• Depression

Interventions

DRUG

Buprenorphine

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.

DRUG

Naltrexone

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.

DRUG

Oral Placebo

Oral placebo: to match the oral naltrexone.

DRUG

IM Placebo

IM saline placebo: to match the i.v. buprenorphine.

DEVICE

Theta burst stimulation (TBS) of the ventromedial prefrontal cortex.

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.

Sponsors & Collaborators

• National Institute of Mental Health (NIMH)

  collaborator NIH

• Marta Peciña, MD PhD

  lead OTHER

Principal Investigators

• Marta Peciña, MD, PhD · University of Pittsburgh

Study Design

Allocation

RANDOMIZED

Purpose

OTHER

Masking

DOUBLE

Model

FACTORIAL

Eligibility

Min Age

18 Years

Max Age

55 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2020-10-19

Primary Completion

2026-01-21

Completion

2026-01-21

FDA Drug

Yes

FDA Device

Yes

Countries

• United States

Study Locations