Rapid Antidepressant Improvement Secondary to Excitatory Brain Responses

Phase 4

Recruiting

• Conditions: Major Depressive Disorder; Depression
• Interventions: Drug: Buprenorphine; Drug: Naltrexone; Drug: Oral Placebo; Drug: IM Placebo; Device: Theta burst stimulation (TBS) of the ventromedial prefrontal cortex.

• Registration Number: NCT04276259
• Lead Sponsor: Marta Peciña, MD PhD

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.

Study Timeline

• Study First Submitted: 2020-02-06
• Study First Submitted QC: 2020-02-18
• Study First Posted: 2020-02-19
• Study Start: 2020-10-19
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-01
• Last Update Posted: 2024-07-03
• Primary Completion: 2026-03-31
• Study Completion: 2026-03-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 120

Inclusion Criteria

• • Adults, age 18-55 years; fluent in English and with the capacity to understand the nature of the study and sign the written informed consent since the research instruments used in this study are not available in other languages;

  • Written informed consent obtained;
  • A score on the Mood and Anxiety Symptom Questionnaire- Anhedonic Depression (MASQ-AD) ≥ 23 (2/3 sample) and MASQ-AD < 23 (1/3 sample) 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.
  • 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;
  • Any reason not listed herein yet, determined by the site PI and research staff that makes participation in the study hazardous.
  • Having any contraindication for the performance of TMS, such as the presence of a neurologic disorder or medication therapy known to alter seizure threshold (e.g., stroke, aneurysm, brain surgery, structural brain lesion, brain injury, frequent/severe headaches), recurrent seizures or epilepsy in participant or family history of hereditary epilepsy, pregnancy, metallic implants in body or other devices that may be affected by magnetic field or significant heart disease or cerebrovascular disease.
  • Having any contraindication for the performance of an MRI, such as the presence of metal implants or foreign metallic objects (e.g., braces or extensive dental work), severe claustrophobia, or inability to tolerate the scanning procedures.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
Buprenorphine Injection + Oral Placebo Pill	Oral Placebo	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	Theta burst stimulation (TBS) of the ventromedial prefrontal cortex.	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 Oral Tablet + Intramuscular Saline Injection	IM Placebo	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	Theta burst stimulation (TBS) of the ventromedial prefrontal cortex.	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.
Oral Placebo Pill + Intramuscular Saline Injection	Oral Placebo	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.
Oral Placebo Pill + Intramuscular Saline Injection	IM Placebo	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.
Oral Placebo Pill + Intramuscular Saline Injection	Theta burst stimulation (TBS) of the ventromedial prefrontal cortex.	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.
Buprenorphine Injection + Oral Placebo Pill	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.
Naltrexone Oral Tablet + Intramuscular Saline Injection	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.

Primary Outcome Measures

Name	Time	Method
Opioid Modulation Effects on BOLD Responses in the vmPFC-VS circuit	Approximately at day 7, 14, 21.	Changes in BOLD signal during the Antidepressant fMRI Task between Buprenorphine vs. inert pill, and Naltrexone vs. inert pill.
BOLD Responses in the vmPFC-VS circuit	Approximately at day 7, 14, 21.	Changes in blood oxygenation level-dependent (BOLD) signal during the Antidepressant fMRI Task.
TBS Effects of BOLD Response	Approximately at day 7, 14, 21.	Changes in BOLD signal during the Antidepressant fMRI Task between iTBS vs. sTBS, and cTBS vs. sTBS.

Trial Locations

Locations (1)

Bellefield Tower; 🇺🇸 Pittsburgh, Pennsylvania, United States