Depression, Major Depressive Disorder
Conditions
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.
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.
Interventions
DRUGNaltrexone 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).
DRUGPlacebo 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.
Sponsors
Brain & Behavior Research Foundation
Marta Peciña, MD PhD
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Masking description
Double-blinded
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Naltrexone, Then Placebo 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. | 10 |
| Placebo, Then Naltrexone 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. | 10 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (1 Day) | Withdrawal by Subject | 1 | 1 |
| Washout (1 Week) | Lost to Follow-up | 1 | 2 |
Baseline characteristics
| Characteristic | Naltrexone, Then Placebo | Placebo, Then Naltrexone | Total |
|---|---|---|---|
| Age, Continuous | 25.3 years STANDARD_DEVIATION 5.2 | 25.9 years STANDARD_DEVIATION 8.2 | 25.6 years STANDARD_DEVIATION 6.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 10 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 10 participants | 10 participants | 20 participants |
| Sex: Female, Male Female | 8 Participants | 9 Participants | 17 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 23 | 0 / 24 |
| other Total, other adverse events | 10 / 23 | 14 / 24 |
| serious Total, serious adverse events | 0 / 23 | 0 / 24 |
Outcome results
Primary
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.
Time frame: [Approximately at day 1, 7]
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| fMRI BOLD Responses in the rACC Cortex (Placebo Session) | BOLD Responses in the rACC Cortex During the Processing of Contextual Cues at Baseline (Post-placebo) | 0.47 BOLD signal | Standard Deviation 0.76 |
Comparison: Changes in BOLD signal in the rACC during the processing of contextual cues (pleasant \> unpleasant).p-value: 0.01t-test, 2 sided
Primary
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.
Time frame: [Approximately at day 1, 7]
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| fMRI BOLD Responses in the rACC Cortex (Placebo Session) | Naltrexone-induced Changes in BOLD Responses in the rACC Cortex During the Processing of Contextual Cues (Placebo vs. Naltrexone) | 1.23 changes in BOLD signal | Standard Deviation 1.07 |
Comparison: Changes in BOLD fMRI signal from the Placebo vs. the Naltrexone session.p-value: 0.0002t-test, 2 sided