SONRISA2: Study of Naltrexone-Induced Blockade of Antidepressant Effects

• Sponsor: Marta Peciña, MD PhD (Other)
• Overall Status: Completed
• CT.gov ID: NCT04322526
• Collaborator: Brain & Behavior Research Foundation (Other)
• Enrollment: 25
• Location: 1
• Arms: 2
• Actual Duration (Months): 12.5
• Patients Per Site Per Month: 2

Study Details

Study Description

Brief Summary

The goal of this study is to determine whether antidepressant placebo effects and contextual cues broadly, can be blocked by one single dose of the µ-opioid antagonist naltrexone. To test this hypothesis, un-medicated, patients with MDD completed a randomized, double-blind, placebo-controlled, cross-over study of 50mg of the µ-opioid antagonist naltrexone or matching placebo, immediately before a Pharmaco-fMRI scanning session.

Condition or Disease	Intervention/Treatment	Phase
Depression; Major Depressive Disorder	Drug: Naltrexone 50 Mg Oral Tablet; Drug: Placebo oral tablet	Phase 4

Detailed Description

Neuroimaging offers a precise and objective way to characterize the neural and molecular basis of the antidepressant response in humans. Furthermore, the combination of neuroimaging with pharmacological manipulations opens the possibility of investigating drug-induced brain changes associated with behavioral responses.

In this study, the investigators aimed to whether antidepressant placebo effects and contextual cues broadly can be blocked by one single dose of the µ-opioid antagonist naltrexone. To assess trial by trial manipulation of antidepressant placebo effects inside of the scanner, the investigators have developed and piloted an fMRI task, specifically designed to record and modulate mood improvement using simulated neurofeedback. In a pilot study using this task, patients with MDD who reported acute mood improvement in response to positive neurofeedback, showed increased blood-oxygen-level-dependent (BOLD) responses in the ACC, and in particular, the rostral ACC (rACC), a reliable marker of treatment response in depression, and analgesic effects. In summary, these preliminary studies demonstrate 1) the contribution of the opioid system to the formation of antidepressant effects in MDD; and 2) increased rACC BOLD responses in patients who reported acute mood improvement induced by positive neurofeedback after a fast-acting antidepressant.

Still, the opioid modulation of acute mood improvement and rACC BOLD responses in patients with MDD has not been investigated, which justifies the research proposed in this application. Based on this preliminary evidence, The investigators hypothesize that antidepressant effects in patients with Major Depression rely on opioid modulation of rACC activity, and therefore can be partially or totally blocked using the selective µ-opioid antagonist naltrexone.To test this hypothesis, 20 un-medicated, patients with MDD completed a randomized, double-blind, placebo-controlled, cross-over study of 50mg of the µ-opioid antagonist naltrexone or matching placebo, immediately before a Pharmaco-fMRI scanning session. The study aims to:

AIM 1: Evaluate the effect of naltrexone on acute mood improvement and rostral anterior cingulate (rACC) BOLD activity induced by positive neurofeedback after a fast-acting antidepressant. The investigators hypothesize that naltrexone-induced blockade of µ-opioid receptors will reverse the acute mood improvement and increased rACC BOLD activity induced by positive neurofeedback.

AIM 2: Determine the extent to which individual differences in the rACC BOLD activity induced by positive neurofeedback after a fast-acting antidepressant predict acute mood improvement. The investigators hypothesize that increased rACC BOLD activity induced by positive neurofeedback will be associated with greater acute mood improvement.

AIM 3: Define the role of the rACC BOLD activity induced by positive neurofeedback as a mediator of the effect of group (naltrexone versus placebo) in acute mood improvement.

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: This is a pharmaco-fMRI study of one single dose of naltrexone or placebo followed by an fMRI session in a crossover design.This is a pharmaco-fMRI study of one single dose of naltrexone or placebo followed by an fMRI session in a crossover design.
• Masking: Double (Participant, Investigator)
• Masking Description: Double-blinded
• Primary Purpose: Basic Science
• Official Title: Naltrexone-induced Blockade of Neural Responses Induced by Fast-Acting Antidepressant Effects
• Actual Study Start Date: Jul 1, 2017
• Actual Primary Completion Date: Jul 15, 2018
• Actual Study Completion Date: Jul 15, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Naltrexone, then placebo Naltrexone is thought to strongly block μ-opioid receptors. Oral (pill) opioid antagonist which will be used to modulate neural responses during the Contextual Framing and the Antidepressant fMRI Task.	Drug: Naltrexone 50 Mg Oral Tablet; Naltrexone hydrochloride (ReVia®. Toronto, ON: Teva Canada Limited; 2015) (onset of action: ≥15 minutes; peak effect: ~1 hour; duration: ~24 hours).; Drug: Placebo oral tablet; Placebo tablet that has no inherent power to produce an effect. In the inert pill condition, participants will receive an oral placebo tablet.
Placebo Comparator: Placebo, then naltrexone In the naltrexone condition, participants will receive one tablet of 50mg Naltrexone hydrochloride.	Drug: Naltrexone 50 Mg Oral Tablet; Naltrexone hydrochloride (ReVia®. Toronto, ON: Teva Canada Limited; 2015) (onset of action: ≥15 minutes; peak effect: ~1 hour; duration: ~24 hours).; Drug: Placebo oral tablet; Placebo tablet that has no inherent power to produce an effect. In the inert pill condition, participants will receive an oral placebo tablet.

Outcome Measures

Primary Outcome Measures

1. BOLD Responses in the rACC Cortex During the Processing of Contextual Cues at Baseline (Post-placebo) [[Approximately at day 1, 7]]

   In order to identify the neural correlates of contextual processing, we examined changes in blood oxygenation level-dependent (BOLD) signal during the post-placebo fMRI scanning session.

2. Naltrexone-induced Changes in BOLD Responses in the rACC Cortex During the Processing of Contextual Cues (Placebo vs. Naltrexone) [[Approximately at day 1, 7]]

   In order to identify naltrexone-induced changes in the neural correlates of contextual processing, we examined changes in blood oxygenation level-dependent (BOLD) during the fMRI scanning session between Naltrexone vs. placebo pill.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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;

• Outpatients with a current primary diagnosis of nonpsychotic Major Depressive Disorder (MDD) per the Mini-International Neuropsychiatric Interview (M.I.N.I) with or without certain anxiety disorders (e.g., generalized anxiety, panic, agoraphobia, social phobia, and specific phobia); HDRS-17 score of ≥ 16 at Screening Visit;

• 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 will need to be antidepressant medication-free for at least 21 days prior to the collection of imaging data (five weeks for fluoxetine). However, individuals currently taking antidepressants will not be eligible to enroll in the study, even if they are willing to stop their medications.

Exclusion Criteria:

• Currently taking opioid analgesics or in acute opioid withdraw.

• 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);

• Requiring medications for their GMCs that contraindicate treatment with naltrexone;

• Having epilepsy or other conditions requiring an anticonvulsant;

• Receiving or have received during the current episode vagus nerve stimulation, ECT, or rTMS.

• 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 CBT 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;

• 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 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Bellefield Towers	Pittsburgh	Pennsylvania	United States	15213

Sponsors and Collaborators

• Marta Peciña, MD PhD
• Brain & Behavior Research Foundation

Investigators

• Principal Investigator: Marta Peciña, MD, PhD, University of Pittsburgh

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 30, 2020

More Information

Publications

None provided.

• Responsible Party: Marta Peciña, MD PhD, Assistant Professor, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT04322526
• Other Study ID Numbers: PRO16050133
• First Posted: Mar 26, 2020
• Last Update Posted: Apr 21, 2020
• Last Verified: Apr 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Depressive Disorder; Depressive Disorder, Major; Naltrexone

Study Results

Participant Flow

Arm/Group Title	Naltrexone, Then Placebo	Placebo, Then Naltrexone
Arm/Group Description	In the naltrexone and then placebo arm, participants receive one-dose naltrexone 50mg one hour before a first fMRI scanning session on visit 1 followed by a one-dose placebo pill one hour before a second fMRI scanning session on visit 2. Naltrexone 50 Mg Oral Tablet: Naltrexone hydrochloride (ReVia®. Toronto, ON: Teva Canada Limited; 2015) (onset of action: ≥15 minutes; peak effect: ~1 hour; duration: ~24 hours). Placebo oral tablet: Placebo tablet that has no inherent power to produce an effect. In the inert pill condition, participants will receive an oral placebo tablet.	In the placebo and then naltrexone arm, participants receive one-dose of placebo pill one hour before a first fMRI scanning session on visit 1 followed by a one-dose naltrexone 50mg one hour before a second fMRI scanning session on visit 2. Naltrexone 50 Mg Oral Tablet: Naltrexone hydrochloride (ReVia®. Toronto, ON: Teva Canada Limited; 2015) (onset of action: ≥15 minutes; peak effect: ~1 hour; duration: ~24 hours). Placebo oral tablet: Placebo tablet that has no inherent power to produce an effect. In the inert pill condition, participants will receive an oral placebo tablet.
Period Title: First Intervention (1 Day)
STARTED	13	12
COMPLETED	12	11
NOT COMPLETED	1	1
Period Title: First Intervention (1 Day)
STARTED	12	11
COMPLETED	11	9
NOT COMPLETED	1	2
Period Title: First Intervention (1 Day)
STARTED	11	9
COMPLETED	11	9
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Naltrexone, Then Placebo	Placebo, Then Naltrexone	Total
Arm/Group Description	In the naltrexone and then placebo arm, participants receive one-dose naltrexone 50mg one hour before a first fMRI scanning session on visit 1 followed by a one-dose placebo pill one hour before a second fMRI scanning session on visit 2. Naltrexone 50 Mg Oral Tablet: Naltrexone hydrochloride (ReVia®. Toronto, ON: Teva Canada Limited; 2015) (onset of action: ≥15 minutes; peak effect: ~1 hour; duration: ~24 hours). Placebo oral tablet: Placebo tablet that has no inherent power to produce an effect. In the inert pill condition, participants will receive an oral placebo tablet.	In the placebo and then naltrexone arm, participants receive one-dose of placebo pill one hour before a first fMRI scanning session on visit 1 followed by a one-dose naltrexone 50mg one hour before a second fMRI scanning session on visit 2. Naltrexone 50 Mg Oral Tablet: Naltrexone hydrochloride (ReVia®. Toronto, ON: Teva Canada Limited; 2015) (onset of action: ≥15 minutes; peak effect: ~1 hour; duration: ~24 hours). Placebo oral tablet: Placebo tablet that has no inherent power to produce an effect. In the inert pill condition, participants will receive an oral placebo tablet.	Total of all reporting groups
Overall Participants	10	10	20
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	25.3 (5.2)	25.9 (8.2)	25.6 (6.6)
Sex: Female, Male (Count of Participants)
Female	8 80%	9 90%	17 85%
Male	2 20%	1 10%	3 15%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	10 100%	10 100%	20 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	10 100%	10 100%	20 100%

Outcome Measures

1. Primary Outcome

Title	BOLD Responses in the rACC Cortex During the Processing of Contextual Cues at Baseline (Post-placebo)
Description	In order to identify the neural correlates of contextual processing, we examined changes in blood oxygenation level-dependent (BOLD) signal during the post-placebo fMRI scanning session.
Time Frame	[Approximately at day 1, 7]

Outcome Measure Data

Analysis Population Description

The goal of aim one was to identify the neural correlates of antidepressant placebo effects. This aim was accomplished by examining the neural responses to the Antidepressant placebo fMRI task during the placebo session only, regardless of whether participants were assigned to the placebo-naltrexone or the naltrexone-placebo intervention.

Arm/Group Title	fMRI BOLD Responses in the rACC Cortex (Placebo Session)
Arm/Group Description	We examined baseline brain measures of contextual processing during the placebo session only. In particular, we obtained whole-brain BOLD fMRI responses during the processing of contextual cues and extracted BOLD signal measures in the rACC. Post-naltrexone brain responses were not used for this analysis.
Measure Participants	20
Mean (Standard Deviation) [BOLD signal]	0.47 (0.76)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	fMRI BOLD Responses in the rACC Cortex (Placebo Session)
	Comments	Changes in BOLD signal in the rACC during the processing of contextual cues (pleasant > unpleasant).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	t-test, 2 sided
	Comments

2. Primary Outcome

Title	Naltrexone-induced Changes in BOLD Responses in the rACC Cortex During the Processing of Contextual Cues (Placebo vs. Naltrexone)
Description	In order to identify naltrexone-induced changes in the neural correlates of contextual processing, we examined changes in blood oxygenation level-dependent (BOLD) during the fMRI scanning session between Naltrexone vs. placebo pill.
Time Frame	[Approximately at day 1, 7]

Outcome Measure Data

Analysis Population Description

The goal of aim two was to investigate the effects of one single dose of naltrexone on the neural correlates of antidepressant placebo effects. This aim was accomplished by examining changes in the neural responses to the Antidepressant placebo fMRI task from the naltrexone to the placebo session, regardless of the order of each intervention.

Arm/Group Title	fMRI BOLD Responses in the rACC Cortex (Naltrexone vs Placebo)
Arm/Group Description	We examined naltrexone-induced changes in brain signal during the processing of contextual cues by extracting brain responses in the rACC and comparing then during the baseline (placebo only) and the naltrexone session using paired-t test statistical analysis.
Measure Participants	17
Mean (Standard Deviation) [changes in BOLD signal]	1.23 (1.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	fMRI BOLD Responses in the rACC Cortex (Placebo Session)
	Comments	Changes in BOLD fMRI signal from the Placebo vs. the Naltrexone session.
	Type of Statistical Test	Other
	Comments	Mechanistic hypothesis: naltrexone will block contextual processing.
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	[Approximately at day 1, 7]
Arm/Group Title	Placebo		Naltrexone
Arm/Group Description	Placebo oral tablet: Placebo tablet that has no inherent power to produce an effect. In the inert pill condition, participants will receive an oral placebo tablet.		Naltrexone 50 Mg Oral Tablet: Naltrexone hydrochloride (ReVia®. Toronto, ON: Teva Canada Limited; 2015) (onset of action: ≥15 minutes; peak effect: ~1 hour; duration: ~24 hours).
All Cause Mortality
	Placebo		Naltrexone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/24 (0%)
Serious Adverse Events
	Placebo		Naltrexone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/24 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Naltrexone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/23 (43.5%)		14/24 (58.3%)
Gastrointestinal disorders
Nausea, gastrointestinal discomfort, vomiting.	3/23 (13%)	3	8/24 (33.3%)	8
Nervous system disorders
Fatigue	6/23 (26.1%)	6	10/24 (41.7%)	10
Dizziness/drowsiness	4/23 (17.4%)	4	5/24 (20.8%)	5
Shaking	1/23 (4.3%)	1	0/24 (0%)	0

Limitations/Caveats

This study does not have a healthy control condition, and therefore, results cannot be generalized beyond depression.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.