Rapid Antidepressant Improvement Secondary to Excitatory Brain Responses

NCT04276259 | Completed Phase 4 FDA Drug FDA Device

• 2 other identifiers: STUDY190503071R01MH122548-01
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

Brief 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

Outcome Measures

Primary Outcomes (3)

• BOLD Responses in the vmPFC-VS circuit

  Changes in blood oxygenation level-dependent (BOLD) signal during the Antidepressant fMRI Task.

  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.

  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.

  Approximately at day 7, 14, 21.

Study Arms (3)

Buprenorphine Injection + Oral Placebo Pill

EXPERIMENTAL

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: Buprenorphine; Drug: Oral Placebo; Device: Theta burst stimulation (TBS) of the ventromedial prefrontal cortex.

Naltrexone Oral Tablet + Intramuscular Saline Injection

EXPERIMENTAL

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: Naltrexone; Drug: IM Placebo; Device: Theta burst stimulation (TBS) of the ventromedial prefrontal cortex.

Oral Placebo Pill + Intramuscular Saline Injection

EXPERIMENTAL

Inert pill and saline injection that have no inherent power to produce an effect. In the inert pill condition, participants will receive one IM arm injection of saline (1ML) and an oral placebo tablet.

Drug: Oral Placebo; Drug: IM Placebo; Device: Theta burst stimulation (TBS) of the ventromedial prefrontal cortex.

Interventions

Oral Placebo DRUG

Oral placebo: to match the oral naltrexone.

Buprenorphine Injection + Oral Placebo Pill; Oral Placebo Pill + Intramuscular Saline Injection

IM Placebo DRUG

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

Naltrexone Oral Tablet + Intramuscular Saline Injection; Oral Placebo Pill + Intramuscular Saline Injection

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

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.

Also known as: sham (s), continuous (c) and intermittent (i).

Buprenorphine Injection + Oral Placebo Pill; Naltrexone Oral Tablet + Intramuscular Saline Injection; Oral Placebo Pill + Intramuscular Saline Injection

Buprenorphine DRUG

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.

Buprenorphine Injection + Oral Placebo Pill

Naltrexone DRUG

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.

Naltrexone Oral Tablet + Intramuscular Saline Injection

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Adults, age 18-55 years; fluent in English;
• Written informed consent obtained;
• Depressive symptoms with or without certain anxiety disorders (e.g., generalized anxiety, panic, agoraphobia, social phobia, and specific phobia);
• No more than one failed antidepressant trial of adequate dose and duration, as defined by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ);
• Participants can have previous history of antidepressant treatment but will need to be antidepressant medication-free for at least 21 days prior to the collection of imaging data (five weeks for fluoxetine).

You may not qualify if:

• Pregnant or breastfeeding or plan to become pregnant over the duration of the study;
• History (lifetime) of psychotic depressive, schizophrenic, bipolar (I, II, or NOS), schizoaffective, or other Axis I psychotic disorders;
• Meeting M.I.N.I. criteria for substance dependence in the last 6 months, except for nicotine, or substance abuse in the last 2 months;
• Requiring immediate hospitalization for psychiatric disorder or have an unstable general medical condition (GMC) that will likely require hospitalization or to be deemed terminal (life expectancy \< 6 months after study entry);
• Having epilepsy or other conditions requiring an anticonvulsant;
• Receiving vagus nerve stimulation, electroconvulsive therapy, or repetitive Transcranial Magnetic Stimulation during the current episode.
• Currently taking any psychiatric medication or other potential augmenting agents (e.g., T3 in the absence of thyroid disease, lithium, buspirone); Taking thyroid medication for hypothyroidism may be included only if they have been stable on the thyroid medication for 3 months;
• Receiving therapy that is depression specific, such as Cognitive Behavioral Therapy or Interpersonal Psychotherapy of Depression (participants can participate if they are receiving psychotherapy that is not targeting the symptoms of depression, such as supportive therapy, marital therapy);
• Currently actively suicidal or considered a high suicide risk;
• Patients are receiving opioid analgesics.
• Patients are currently dependent on opioids.
• Patients are in acute opioid withdrawal.
• Any individual who has failed the naloxone challenge test or who has a positive urine screen for opioids.
• Any individual with a history of sensitivity to buprenorphine or naltrexone.
• Currently enrolled in another study, and participation in that study contraindicates participation in this study;

Sponsors & Collaborators

• Marta Peciña, MD PhD: lead
• National Institute of Mental Health (NIMH): collaborator

Study Sites (1)

Bellefield Tower

Pittsburgh, Pennsylvania, 15213, United States

Location

Related Publications (1)

• Pecina M, Dombrovski AY, Price R, Karim HT. Understanding the Neurocomputational Mechanisms of Antidepressant Placebo Effects. J Psychiatr Brain Sci. 2021;6:e210001. doi: 10.20900/jpbs.20210001. Epub 2021 Feb 15.

  PMID: 33732892 DERIVED

MeSH Terms

Conditions

Depressive Disorder, Major; Depression

Interventions

Buprenorphine; Naltrexone

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Naloxone

Study Officials

• Marta Peciña, MD, PhD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: OTHER
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor

Model Details: This is a mechanistic trial.

Study Record Dates

• First Submitted: February 6, 2020
• First Posted: February 19, 2020
• Study Start: October 19, 2020
• Primary Completion: January 21, 2026
• Study Completion: January 21, 2026
• Last Updated: February 13, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, ANALYTIC CODE
• Time Frame: Immediately following publication. No end date.
• Access Criteria: Anyone who wishes to access the data.

Locations

US (1)