DepressionPhase 4SONRISA2NCT04322526

Study of Naltrexone-Induced Blockade of Antidepressant Effects

A Phase 4 study testing Naltrexone 50 Mg Oral Tablet in people with Depression and Major Depressive Disorder, run by Marta Peciña, MD PhD at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 to 55 years
Conditions the study is for: Depression, Major Depressive Disorder
What is being tested?: Naltrexone 50 Mg Oral Tablet
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 25 participants
Where: 1 siteUnited States
Study dates: 1 Jul 2017to 15 Jul 2018
Phase: Phase 4
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 55 years
All sexes
No healthy volunteers
Adult

Who may be able to join

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.

Who cannot join

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;

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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.

Trial locations and contacts

1 site in 1 country.

United States1 site

Bellefield Towers
Pittsburgh, Pennsylvania, 15213

Other trials in United States

About this study

Official title: Naltrexone-induced Blockade of Neural Responses Induced by Fast-Acting Antidepressant Effects

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.

Read the 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.

Conditions: Depression, Major Depressive Disorder
Being tested: Naltrexone 50 Mg Oral Tablet, Placebo oral tablet
Medical subject headings: Depression, Depressive Disorder, Major

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Naltrexone 50 Mg Oral TabletDrug
Naltrexone hydrochloride (ReVia®. Toronto, ON: Teva Canada Limited; 2015) (onset of action: ≥15 minutes; peak effect: ~1 hour; duration: ~24 hours).
Placebo oral tabletDrug
Placebo tablet that has no inherent power to produce an effect. In the inert pill condition, participants will receive an oral placebo tablet.

Study groups in NCT04322526
Study group	Role	What they receive
Naltrexone, then placebo	Experimental	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. Receives: Drug: Naltrexone 50 Mg Oral Tablet; Drug: Placebo oral tablet
Placebo, then naltrexone	Placebo comparator	In the naltrexone condition, participants will receive one tablet of 50mg Naltrexone hydrochloride. Receives: Drug: Naltrexone 50 Mg Oral Tablet; Drug: Placebo oral tablet

What is being measured

The primary outcome is the main question the study is designed to answer.

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

1 Jul 201715 Jul 2018

First posted26 Mar 2020
Study start1 Jul 2017
Primary completion15 Jul 2018
Study completion15 Jul 2018

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for DepressionStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 4
Primary purpose: Basic science
Allocation: Randomised
Intervention model: Crossover
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.
Masking: Double blind
Who is masked: Participant, Investigator
Enrolment: 25 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT04322526
Sponsor's protocol ID: PRO16050133
Acronym: SONRISA2
Status last verified: Apr 2020
First submitted: 23 Mar 2020
Last updated: 21 Apr 2020
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: Yes: NIfTI-formatted images for imaging, documentation, and code (https://github.com/) developed as part of this project will be shared upon request.

Publications

Chen J, Mizuno A, Lyew T, Karim HT, Karp JF, Dombrovski AY, Pecina M. Naltrexone modulates contextual processing in depression. Neuropsychopharmacology. 2020 Nov;45(12):2070-2078. doi: 10.1038/s41386-020-00809-2. Epub 2020 Aug 25.
PubMed 32843703

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 21 Apr 2020. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Naltrexone-induced Blockade of Neural Responses Induced by Fast-Acting Antidepressant Effects
ClinicalTrials.gov ID: NCT04322526
Acronym / sponsor ID: SONRISA2 / PRO16050133
Conditions: Depression, Major Depressive Disorder
Phase: Phase 4
Study type: Interventional
Recruitment status: Completed
Enrolment: 25 participants (actual)
Lead sponsor: Marta Peciña, MD PhDUniversity, hospital or other
Collaborators: Brain & Behavior Research Foundation
Study start: 1 Jul 2017 (actual)
Primary completion: 15 Jul 2018 (actual)
Study completion: 15 Jul 2018 (actual)
First posted: 26 Mar 2020 (actual)
Results: Posted 21 Apr 2020

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

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

Primary purpose: Basic science
Allocation: Randomised
Intervention model: Crossover
Masking: Double blind (participant, investigator)
Number of arms: 2
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.

Arm	Type	Receives
Naltrexone, then placebo	Experimental	Drug: Naltrexone 50 Mg Oral Tablet, Drug: Placebo oral tabletNaltrexone 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.
Placebo, then naltrexone	Placebo comparator	Drug: Naltrexone 50 Mg Oral Tablet, Drug: Placebo oral tabletIn the naltrexone condition, participants will receive one tablet of 50mg Naltrexone hydrochloride.

Who may qualify

Ages: 18 to 55 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult

Key inclusion criteria (5 listed)

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.

Key exclusion criteria (14 listed)

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);

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Naltrexone 50 Mg Oral TabletNaltrexone hydrochloride (ReVia®. Toronto, ON: Teva Canada Limited; 2015) (onset of action: ≥15 minutes; peak effect: ~1 hour; duration: ~24 hours).	Drug	Naltrexone, then placebo, Placebo, then naltrexone
Placebo oral tabletPlacebo tablet that has no inherent power to produce an effect. In the inert pill condition, participants will receive an oral placebo tablet.	Drug	Naltrexone, then placebo, Placebo, then naltrexone

Primary outcome

BOLD Responses in the rACC Cortex During the Processing of Contextual Cues at Baseline (Post-placebo)
Time frame: [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.
Naltrexone-induced Changes in BOLD Responses in the rACC Cortex During the Processing of Contextual Cues (Placebo vs. Naltrexone)
Time frame: [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.

Results and safety

Results posted to the registry on 21 Apr 2020, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Naltrexone, Then Placebo	13	12
Placebo, Then Naltrexone	12	11

Primary outcome: BOLD Responses in the rACC Cortex During the Processing of Contextual Cues at Baseline (Post-placebo)

Time frame: [Approximately at day 1, 7]. Mean (Standard Deviation). Unit: BOLD signal

Measure	fMRI BOLD Responses in the rACC Cortex (Placebo Session) n = 20
Value	0.47 (0.76)

fMRI BOLD Responses in the rACC Cortex (Placebo Session): p = 0.01, t-test, 2 sided

Population analysed: 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.

Primary outcome: Naltrexone-induced Changes in BOLD Responses in the rACC Cortex During the Processing of Contextual Cues (Placebo vs. Naltrexone)

Time frame: [Approximately at day 1, 7]. Mean (Standard Deviation). Unit: changes in BOLD signal

Measure	fMRI BOLD Responses in the rACC Cortex (Naltrexone vs Placebo) n = 17
Value	1.23 (1.07)

fMRI BOLD Responses in the rACC Cortex (Naltrexone vs Placebo): p = 0.0002, t-test, 2 sided

Population analysed: 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.

Adverse events

Time frame: [Approximately at day 1, 7]. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Placebo	0 of 23 (0%)	10 of 23 (43.5%)	0 of 23
Naltrexone	0 of 24 (0%)	14 of 24 (58.3%)	0 of 24

Limitations and caveats (from the sponsor): This study does not have a healthy control condition, and therefore, results cannot be generalized beyond depression.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 21 Apr 2020.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 32843703Chen J, Mizuno A, Lyew T, Karim HT, Karp JF, Dombrovski AY, Pecina M. Naltrexone modulates contextual processing in depression. Neuropsychopharmacology. 2020 Nov;45(12):2070-2078. doi: 10.1038/s41386-020-00809-2. Epub 2020 Aug 25.
Individual participant dataSharing planned: Yes. NIfTI-formatted images for imaging, documentation, and code (https://github.com/) developed as part of this project will be shared upon request.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Marta Peciña, MD, PhD principal investigator

University of Pittsburgh

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Naltrexone 50 Mg Oral Tablet in people with Depression and Major Depressive Disorder, run by Marta Peciña, MD PhD at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 21 Apr 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 21 Apr 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

BOLD Responses in the rACC Cortex During the Processing of Contextual Cues at Baseline (Post-placebo) (time frame: [Approximately at day 1, 7]). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04322526, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Apr 2020.