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.

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.

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.

NIfTI-formatted images for imaging, documentation, and code (https://github.com/) developed as part of this project will be shared upon request.

Immediately following publication upon request. No end date.

Anyone who wishes to access the data.

[Approximately at day 1, 7]

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

Double-blinded