Neurocomputational Mechanisms of Mood Improvement

Marta Peciña, MD PhD1 site in 1 country120 target enrollmentOctober 19, 2020

ConditionsMajor Depressive Disorder Depression

InterventionsOral Placebo Buprenorphine Theta burst stimulation (TBS) of the ventromedial prefrontal cortex.Naltrexone IM Placebo

Overview

Phase: Phase 4
Intervention: Oral Placebo
Conditions: Major Depressive Disorder
Sponsor: Marta Peciña, MD PhD
Enrollment: 120
Locations: 1
Primary Endpoint: Opioid Modulation Effects on BOLD Responses in the vmPFC-VS circuit
Status: Completed
Last Updated: 2 months ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

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).

Detailed Description

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.

Registry

clinicaltrials.gov

Start Date

October 19, 2020

End Date

January 21, 2026

Last Updated

2 months ago

Study Type

Interventional

Study Design

Factorial

Sex

All

Investigators

Sponsor

Marta Peciña, MD PhD

Responsible Party

Sponsor Investigator

Principal Investigator

Marta Peciña, MD PhD

Associate Professor

University of Pittsburgh

Eligibility Criteria

Inclusion Criteria

•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).

Exclusion Criteria

•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.

Arms & Interventions

Oral Placebo Pill + Intramuscular Saline Injection

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.

Intervention: Oral Placebo

Buprenorphine Injection + Oral Placebo Pill

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.

Intervention: Buprenorphine

Buprenorphine Injection + Oral Placebo Pill

Intervention: Oral Placebo

Buprenorphine Injection + Oral Placebo Pill

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

Naltrexone Oral Tablet + Intramuscular Saline Injection

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.

Intervention: Naltrexone