A Phase 2 interventional study of Naltrexone and Placebo in Major Depressive Disorder, Depression, Unipolar and Recurrence, sponsored by Massachusetts General Hospital. Completed at 1 site in United States. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2017-02-24.
Sponsored by Massachusetts General Hospital · Phase 2, Interventional, and Treatment
The purpose of this pilot study is to determine if taking a low dose of naltrexone in addition to an antidepressant medication can help treat relapse or recurrence in people with Major Depressive Disorder (MDD). The U.S. Food and Drug Administration (FDA) has approved naltrexone for the treatment of alcohol dependence and opioid dependence, but the FDA has not approved naltrexone to treat depression. The investigators hypothesize that patients with breakthrough depression on an antidepressant regimen containing a pro-dopaminergic agent assigned to treatment with low dose naltrexone will demonstrate higher rates of response compared to those patients taking placebo.
We carried out a pilot double-blind, randomized, controlled study of low-dose naltrexone (LDN) 1 mg b.i.d. versus placebo augmentation in MDD patients who relapsed on dopaminergic agents. The primary aim was to test the hypothesis that patients experiencing depressive breakthrough would demonstrate greater improvement in their depression when supplementing their current antidepressant regimen with LDN versus placebo, with no significant difference in side effects.
Boston area men and women with MDD were recruited from 01/13/2014-11/11/2014 via Institutional Review Board (IRB)-approved newspaper, television, internet, and radio ads initiated by Massachusetts General Hospital (MGH) and Boston Clinical Trials (BCT). Screened and eligible patients returned one week later for a baseline visit and were randomized consecutively to double-blind treatment with placebo or LDN 1 mg b.i.d. The randomization list was generated by an online randomization program and maintained by the research pharmacist. Subjects were treated for 3 weeks, with weekly assessments. All subjects were required to continue on their baseline antidepressant regimen without changes for the duration of the study; they were likewise asked not to modify any other allowed baseline medications that they had been taking prior to entering the study. Adherence was determined by weekly pill counts; protocol violation was defined as less than 80% adherence.
Side effects were assessed at every visit using the Systematic Assessment for Treatment Emergent Effects-Specific Inquiry (SAFTEE-SI) scale (Levine and Schooler, 1992) and categorized by severity as: 0-none, 1-mild, 2-moderate, 3-severe. Because some SAFTEE items could be present at baseline, particularly in a sample of subjects taking antidepressants that could themselves produce side effects, we defined as treatment-emergent any SAFTEE side effect for which severity increased by two or more levels (e.g. from none to moderate or from mild to severe) from baseline (Mischoulon et al., 2014). Frequency of side effect was based on the number of patients reporting the side effect at any time during the study.
Suicidal ideation was assessed at each visit using the Hamilton Depression Rating Scale (HAM-D). Subjects considered to be at high risk for suicide were discontinued and referred for further evaluation and hospitalization if clinically indicated. Subjects were also discontinued for any emergence of hypomania, mania, or psychosis; a Clinical Global Improvement (CGI-I) score greater than 5 (e.g., score of 6 or 7); evidence of illicit drug use or problematic alcohol use.
At the end of the double-blind study, both responders and non-responders who completed the double-blind phase had the option of receiving open-label adjunctive treatment with LDN for 3 more weeks.
Paired and independent samples t-tests and their nonparametric counterparts (Wilcoxon's signed ranks and Mann-Whitney U tests) were used to examine and compare outcomes for each treatment arm. All analyses were two-tailed. Response and remission rates, and emergence of side effects were compared by Fisher's exact test. Effect sizes (ES) were calculated by Cohen's d (Cohen, 1988), for between-subjects comparisons (changes in depression scales from baseline to end for LDN vs. placebo) and for within-subjects comparisons (changes in depression scales from baseline to end for each separate treatment group). Correlation coefficients were calculated for use in within-subjects comparisons. Statistical analyses were carried out using SPSS version 17.0 (SPSS Inc, Chicago, Illinois).
2,805 studies on the registry are indexed under Depressive Disorder, Major; 565 are open to participants now.
This study's enrollment of 12 is below the median of 80 across 2,338 interventional studies indexed under Depressive Disorder, Major.
Browse Depressive Disorder, Major studies →Massachusetts General Hospital is the lead sponsor of 2,582 studies on the registry; 451 are open to participants now.
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Received treatment with either an Selective serotonin re-uptake inhibitors (SSRI) in combination with a dopaminergic agent, or with an antidepressant with a dopaminergic mechanism of action in adequate doses, achieved remission per American College of Neuropsychopharmacology (ACNP) Task Force guidelines for ≥3 months, currently in relapse or recurrence without dose change for at least the past 4 weeks, based on meeting DSM-IV criteria for MDD.
Exclusion Criteria:
In this arm, patients will receive placebo for three weeks.
Drug: Placebo
In this arm, patients will receive low dose naltrexone for three weeks.
Drug: Naltrexone
1 mg of naltrexone will be given twice daily to all patients assigned to active drug.
Also known as: LDN
Placebo identical in appearance to naltrexone will be given twice daily to all patients assigned to placebo.
Change in HAM-D-17 Total Score
Hamilton Depression Scale-17 (HAM-D-17) item. The change in scores depends on the difference between the initial (baseline) score and the final score at the conclusion of the double blind treatment period. There is no formal range of score changes, since they depend on the initial and final score. A negative score represents a lowering in the score from baseline to end (improvement), and a positive score indicates an increase in score from baseline to end (worsening). A zero score would indicate no change. In theory, the maximum drop in score would be from 52 to zero, or -52. A maximum increase would be from 18 (the minimum score required for admission) to 52, or +34.
Time frame: Change from baseline to week 3
Change in HAM-D28 Total Score
Hamilton Depression Scale-28 item. The change in scores depends on the difference between the initial (baseline) score and the final score at the conclusion of the double blind treatment period. There is no formal range of score changes, since they depend on the initial and final score. A negative score represents a lowering in the score from baseline to end (improvement), and a positive score indicates an increase in score from baseline to end (worsening). A zero score would indicate no change. In theory, the maximum drop in score would be from 81 to zero, or -81. A maximum increase would be from 18 (the minimum score required for admission) to 81, or +63.
Time frame: Change from baseline to week 3
Change in MADRS-10 Total Score
Montgomery-Asberg Depression Rating Scale- 10 item. The change in scores depends on the difference between the initial (baseline) score and the final score at the conclusion of the double blind treatment period. There is no formal range of score changes, since they depend on the initial and final score. A negative score represents a lowering in the score from baseline to end (improvement), and a positive score indicates an increase in score from baseline to end (worsening). A zero score would indicate no change. In theory, the maximum drop in score would be from 60 to zero, or -60. There is no minimum score on the MADRS-10 required for study entry, since the HAMD-17 was the sole entry criteria. However, a score of 18 on the HAMD17 corresponds to approximately a score of 21 on the MADRS-10. A maximum estimated increase would thus be from 21 to 60, or +39.
Time frame: Change from baseline to week 3
Change in MADRS-15 Total Score
Montgomery-Asberg Depression Rating Scale- 15 item. The change in scores depends on the difference between the initial (baseline) score and the final score at the conclusion of the double blind treatment period. There is no formal range of score changes, since they depend on the initial and final score. A negative score represents a lowering in the score from baseline to end (improvement), and a positive score indicates an increase in score from baseline to end (worsening). A zero score would indicate no change. In theory, the maximum drop in score would be from 90 to zero, or -90. There is no minimum score on the MADRS-15 required for study entry, since the HAMD-17 was the sole entry criteria. However, a score of 18 on the HAMD17 corresponds to approximately a score of 21 on the MADRS-10. A maximum estimated increase would thus be from 21 to 90, or +69.
Time frame: Change from baseline to week 3
Change in CGI-S Total Score
Clinical Global Improvement-Severity Scale. The CGI-S score is a one-item scale that measures severity of depression, scored from 1-7, where 1 = no depression is present, 2 = borderline depression, 3 = mild depression, 4 = moderate depression, 5 = marked depression, 6 = severe depression, and 7 = among the most extremely depressed patient. Thus higher scores indicate greater depressive severity. The change in CGI-S score can represent a drop from 7 (maximum severity) to 1 (no depression) or -6. There is no minimum CGI-S score required for admission, but a minimum score of 18 on the HAMD17 corresponds to approximately a score of 4 on the CGI-S. Thus a maximum worsening would be from 4 to 7, or +3.
Time frame: Change from baseline to week 3
Final CGI-I Score
Clinical Global Improvement-Improvement Scale. The CGI-I scale is a one item scale that measures overall change in patient's global condition compared to when they were entered into the study. The scale is graded from 1-7, where 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. Thus higher scores indicate greater worsening, and lower scores indicate greater improvement. The lowest possible score (indicating maximum improvement) is 1, and the highest possible score (indicating greatest worsening) is 7.
Time frame: From baseline to week 3
Response Rate
Response is defined as an improvement in HAM-D-17 score of greater than or equal to 50% compared to baseline score. Response rate is the percent of patients who attain this threshold degree of improvement.
Time frame: Response rate after 3 weeks
Remission Rate
Remission is defined as a final HAM-D-17 score of 7 or less. Remission rate is the percent of patients who attain this threshold score.
Time frame: Remission rate at 3 weeks.
After approval by our Institutional Review Board (IRB), written informed consent was obtained. Boston area men and women with major depressive disorder (MDD) were recruited from 01/13/2014-11/11/2014 via IRB-approved newspaper, television, internet, and radio ads initiated by Massachusetts General Hospital (MGH) and Boston Clinical Trials (BCT).
| Milestone | Placebo | Naltrexone |
|---|---|---|
| Started | 6 | 6 |
| Completed | 6 | 6 |
| Not completed | 0 | 0 |
Hamilton Depression Scale-17 (HAM-D-17) item. The change in scores depends on the difference between the initial (baseline) score and the final score at the conclusion of the double blind treatment period. There is no formal range of score changes, since they depend on the initial and final score. A negative score represents a lowering in the score from baseline to end (improvement), and a positive score indicates an increase in score from baseline to end (worsening). A zero score would indicate no change. In theory, the maximum drop in score would be from 52 to zero, or -52. A maximum increase would be from 18 (the minimum score required for admission) to 52, or +34.
| units on a scale | Placebo | Naltrexone |
|---|---|---|
| Change in HAM-D-17 Total Score | -5.8 ± 5.1 | -9.5 ± 6.9 |
Hamilton Depression Scale-28 item. The change in scores depends on the difference between the initial (baseline) score and the final score at the conclusion of the double blind treatment period. There is no formal range of score changes, since they depend on the initial and final score. A negative score represents a lowering in the score from baseline to end (improvement), and a positive score indicates an increase in score from baseline to end (worsening). A zero score would indicate no change. In theory, the maximum drop in score would be from 81 to zero, or -81. A maximum increase would be from 18 (the minimum score required for admission) to 81, or +63.
| units on a scale | Placebo | Naltrexone |
|---|---|---|
| Change in HAM-D28 Total Score | -6.5 ± 7.4 | -14.6 ± 6.7 |
Montgomery-Asberg Depression Rating Scale- 10 item. The change in scores depends on the difference between the initial (baseline) score and the final score at the conclusion of the double blind treatment period. There is no formal range of score changes, since they depend on the initial and final score. A negative score represents a lowering in the score from baseline to end (improvement), and a positive score indicates an increase in score from baseline to end (worsening). A zero score would indicate no change. In theory, the maximum drop in score would be from 60 to zero, or -60. There is no minimum score on the MADRS-10 required for study entry, since the HAMD-17 was the sole entry criteria. However, a score of 18 on the HAMD17 corresponds to approximately a score of 21 on the MADRS-10. A maximum estimated increase would thus be from 21 to 60, or +39.
| units on a scale | Placebo | Naltrexone |
|---|---|---|
| Change in MADRS-10 Total Score | -7.8 ± 8.5 | -18.2 ± 5.5 |
Montgomery-Asberg Depression Rating Scale- 15 item. The change in scores depends on the difference between the initial (baseline) score and the final score at the conclusion of the double blind treatment period. There is no formal range of score changes, since they depend on the initial and final score. A negative score represents a lowering in the score from baseline to end (improvement), and a positive score indicates an increase in score from baseline to end (worsening). A zero score would indicate no change. In theory, the maximum drop in score would be from 90 to zero, or -90. There is no minimum score on the MADRS-15 required for study entry, since the HAMD-17 was the sole entry criteria. However, a score of 18 on the HAMD17 corresponds to approximately a score of 21 on the MADRS-10. A maximum estimated increase would thus be from 21 to 90, or +69.
| units on a scale | Placebo | Naltrexone |
|---|---|---|
| Change in MADRS-15 Total Score | -10.7 ± 10 | -23.4 ± 6.8 |
Clinical Global Improvement-Severity Scale. The CGI-S score is a one-item scale that measures severity of depression, scored from 1-7, where 1 = no depression is present, 2 = borderline depression, 3 = mild depression, 4 = moderate depression, 5 = marked depression, 6 = severe depression, and 7 = among the most extremely depressed patient. Thus higher scores indicate greater depressive severity. The change in CGI-S score can represent a drop from 7 (maximum severity) to 1 (no depression) or -6. There is no minimum CGI-S score required for admission, but a minimum score of 18 on the HAMD17 corresponds to approximately a score of 4 on the CGI-S. Thus a maximum worsening would be from 4 to 7, or +3.
| units on a scale | Placebo | Naltrexone |
|---|---|---|
| Change in CGI-S Total Score | -0.3 ± 0.8 | -1.3 ± 0.8 |
Clinical Global Improvement-Improvement Scale. The CGI-I scale is a one item scale that measures overall change in patient's global condition compared to when they were entered into the study. The scale is graded from 1-7, where 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. Thus higher scores indicate greater worsening, and lower scores indicate greater improvement. The lowest possible score (indicating maximum improvement) is 1, and the highest possible score (indicating greatest worsening) is 7.
| units on a scale | Placebo | Naltrexone |
|---|---|---|
| Final CGI-I Score | 3.5 ± 0.8 | 2.2 ± 1.2 |
Response is defined as an improvement in HAM-D-17 score of greater than or equal to 50% compared to baseline score. Response rate is the percent of patients who attain this threshold degree of improvement.
| Participants | Placebo | Naltrexone |
|---|---|---|
| Response Rate | 1 | 3 |
Remission is defined as a final HAM-D-17 score of 7 or less. Remission rate is the percent of patients who attain this threshold score.
| Participants | Placebo | Naltrexone |
|---|---|---|
| Remission Rate | 0 | 3 |
Collected over 3 weeks. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Placebo | — | 0/6 (0%) | 6/6 (100%) |
| Naltrexone | — | 0/6 (0%) | 6/6 (100%) |
| Event | Placebo | Naltrexone |
|---|---|---|
| Trouble sleepingNervous system disorders | 0/6 | 2/6 |
| Loss of sexual interestReproductive system and breast disorders | 2/6 | 0/6 |
| Problems with sexual arousalReproductive system and breast disorders | 2/6 | 0/6 |
| Delayed or absent orgasmReproductive system and breast disorders | 2/6 | 0/6 |
| NightmaresNervous system disorders | 1/6 | 0/6 |
| IrritablePsychiatric disorders | 1/6 | 0/6 |
| Hearing or seeing thingsPsychiatric disorders | 0/6 | 1/6 |
| Numbness or tinglingNervous system disorders | 0/6 | 1/6 |
| Dry mouthGastrointestinal disorders | 1/6 | 1/6 |
| Drooling or increased salivationGastrointestinal disorders | 1/6 | 0/6 |
Twenty-one patients were screened, of which twelve patients were admitted into the study, all men and women with major depressive disorder who had relapsed on a pro-dopaminergic antidepressant regimen.
| Age, Categorical(Participants) | Placebo | Naltrexone | Total |
|---|---|---|---|
| <=18 years | 0 | 0 | 0 |
| Between 18 and 65 years | 6 | 6 | 12 |
| >=65 years | 0 | 0 | 0 |
| Age, Continuous(years) | Placebo | Naltrexone | Total |
|---|---|---|---|
| Mean | 43 ± 11 | 47 ± 13 | 45 ± 12 |
| Gender(Participants) | Placebo | Naltrexone | Total |
|---|---|---|---|
| Female | 1 | 3 | 4 |
| Male | 5 | 3 | 8 |
| Ethnicity (NIH/OMB)(Participants) | Placebo | Naltrexone | Total |
|---|---|---|---|
| Hispanic or Latino | 0 | 2 | 2 |
| Not Hispanic or Latino | 5 | 3 | 8 |
| Unknown or Not Reported | 1 | 1 | 2 |
| Race (NIH/OMB)(Participants) | Placebo | Naltrexone | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 1 | 0 | 1 |
| White | 5 | 3 | 8 |
| More than one race | 0 | 1 | 1 |
| Unknown or Not Reported | 0 | 2 | 2 |
| Region of Enrollment(Participants) | Placebo | Naltrexone | Total |
|---|---|---|---|
| United States | 6 | 6 | 12 |
| Hamilton-D-17 score(units on a scale) | Placebo | Naltrexone | Total |
|---|---|---|---|
| Mean | 23.7 ± 2.3 | 21.2 ± 2.0 | 22.4 ± 2.4 |
| Hamilton-D-28 score(units on a scale) | Placebo | Naltrexone | Total |
|---|---|---|---|
| Mean | 26.3 ± 2.6 | 26.2 ± 4.0 | 26.3 ± 3.2 |
3 further baseline measures are reported on the registry.
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