Depression, Unipolar, Major Depressive Disorder, Recurrence, Relapse
Conditions
Keywords
Depression, Recurrence, Relapse, Antidepressants, Naltrexone, Drug augmentation
Brief summary
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.
Detailed description
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).
Interventions
DRUGNaltrexone
1 mg of naltrexone will be given twice daily to all patients assigned to active drug.
DRUGPlacebo
Placebo identical in appearance to naltrexone will be given twice daily to all patients assigned to placebo.
Sponsors
Boston Clinical Trials
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Age 18-65. * Written informed consent. * Meet Diagnostic and Statistical Manual (DSM-IV) criteria by Structured Clinical Interview for DSM-IV (SCID-I/P) for Major Depressive Disorder (MDD), current. * Quick Inventory of Depressive Symptomatology - Self-Rated (QIDS-SR) score of at least 12 at both screen and baseline visits. * 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. 1. Dopaminergic agents here include classical stimulants from the amphetamine or methylphenidate families; dopamine agonists (e.g. pramipexole); or dopamine active antidepressants like bupropion. 2. Additionally, low dose (\< 2.5 mg) Abilify, a D2 partial agonist, is believed to exert pro-dopaminergic effects and will therefore be included as a dopamine agent. 3. Sertraline, although classified as an SSRI, has dopamine reuptake inhibiting properties believed to be relevant at higher doses (\> 150 mg of sertraline), and will also therefore be considered a dopaminergic antidepressant at dose range above. 4. Based on the finding that the norepinephrine transporter is the reuptake inhibitor for dopamine in the prefrontal cortex and the robust sustained clinical response of a patient on duloxetine and low dose naltrexone, we include duloxetine, traditionally classed as an SNRI, among the dopamine acting antidepressants.) * During the baseline visit, patients must be on a stable dose of antidepressant regimen for the past 4 weeks.
Exclusion criteria
* Pregnant women or women of child bearing potential who are not using a medically accepted means of contraception (to include oral contraceptive or implant, condom, diaphragm, spermicide, intrauterine device, tubal ligation, or partner with vasectomy). * Patients who no longer meet DSM-IV criteria for MDD during the baseline visit. * Patients who demonstrate a greater than 25% decrease in depressive symptoms as reflected by the QIDS-SR total score - screen to baseline. * Serious suicide or homicide risk, as assessed by evaluating clinician. * Unstable medical illness including cardiovascular, hepatic, renal, respiratory, endocrine, neurological, or hematological disease. * Substance use disorders active within the last six months, any bipolar disorder (current or past), any psychotic disorder (current or past). * History of a seizure disorder or clinical evidence of untreated hypothyroidism. * Patients requiring excluded medications (including but not limited to chronic or episodic use of anorexiants, episodic hormones, episodic benzodiazepines, episodic insulin, episodic and other episodic psychotropic medications). * Psychotic features in the current episode or a history of psychotic features, as assessed by SCID. * History of naltrexone intolerance at any dose. * Patients with a history of antidepressant-induced hypomania. * Inadequate exposure time or dose of current SSRI or Serotonin-norepinephrine reuptake inhibitor (SNRI); failure to comply with at least 80% of doses.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HAM-D-17 Total Score | Change from baseline to week 3 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in MADRS-10 Total Score | Change from baseline to week 3 | 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. |
| Change in MADRS-15 Total Score | Change from baseline to week 3 | 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. |
| Change in CGI-S Total Score | Change from baseline to week 3 | 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. |
| Change in HAM-D28 Total Score | Change from baseline to week 3 | 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. |
| Response Rate | Response rate after 3 weeks | 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. |
| Remission Rate | Remission rate at 3 weeks. | 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. |
| Final CGI-I Score | From baseline to week 3 | 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. |
Countries
United States
Participant flow
Recruitment details
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).
Pre-assignment details
21 prospective subjects were screened. The following were excluded: sub-threshold Hamilton-D (HAMD) scores (n=3); too recent changes in medication regimen (n=2); cerebrovascular accident in past 5 years (n=1); no history of past treatment response (n=1); inappropriate antidepressant (n=1); antidepressant dose too low and duration too short (n=1).
Participants by arm
| Arm | Count |
|---|---|
| Placebo In this arm, patients will receive placebo for 3 weeks. Placebo identical in appearance to naltrexone will be given twice daily to all patients assigned to placebo. | 6 |
| Naltrexone In this arm, patients will receive active naltrexone for 3 weeks. 1 mg of naltrexone will be given twice daily to all patients assigned to active drug. | 6 |
| Total | 12 |
Baseline characteristics
| Characteristic | Total | Placebo | Naltrexone |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 6 Participants | 6 Participants |
| Age, Continuous | 45 years STANDARD_DEVIATION 12 | 43 years STANDARD_DEVIATION 11 | 47 years STANDARD_DEVIATION 13 |
| Clinical Global Improvement-Severity (CGI-S) score | 4.3 units on a scale STANDARD_DEVIATION 0.5 | 4.3 units on a scale STANDARD_DEVIATION 0.5 | 4.3 units on a scale STANDARD_DEVIATION 0.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 5 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 1 Participants |
| Gender Female | 4 Participants | 1 Participants | 3 Participants |
| Gender Male | 8 Participants | 5 Participants | 3 Participants |
| Hamilton-D-17 score | 22.4 units on a scale STANDARD_DEVIATION 2.4 | 23.7 units on a scale STANDARD_DEVIATION 2.3 | 21.2 units on a scale STANDARD_DEVIATION 2 |
| Hamilton-D-28 score | 26.3 units on a scale STANDARD_DEVIATION 3.2 | 26.3 units on a scale STANDARD_DEVIATION 2.6 | 26.2 units on a scale STANDARD_DEVIATION 4 |
| MADRS-10 score | 30.5 units on a scale STANDARD_DEVIATION 4.3 | 30.7 units on a scale STANDARD_DEVIATION 4.3 | 30.4 units on a scale STANDARD_DEVIATION 4.9 |
| MADRS-15 score | 36.6 units on a scale STANDARD_DEVIATION 4.9 | 36.7 units on a scale STANDARD_DEVIATION 4.2 | 36.6 units on a scale STANDARD_DEVIATION 6.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 8 Participants | 5 Participants | 3 Participants |
| Region of Enrollment United States | 12 Participants | 6 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 6 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 |
Outcome results
Primary
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
Population: Study completers.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in HAM-D-17 Total Score | -5.8 units on a scale | Standard Deviation 5.1 |
| Naltrexone | Change in HAM-D-17 Total Score | -9.5 units on a scale | Standard Deviation 6.9 |
Secondary
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
Population: Study completers.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in CGI-S Total Score | -0.3 units on a scale | Standard Deviation 0.8 |
| Naltrexone | Change in CGI-S Total Score | -1.3 units on a scale | Standard Deviation 0.8 |
Secondary
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
Population: Study subjects who completed the protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in HAM-D28 Total Score | -6.5 units on a scale | Standard Deviation 7.4 |
| Naltrexone | Change in HAM-D28 Total Score | -14.6 units on a scale | Standard Deviation 6.7 |
Secondary
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
Population: Study completers.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in MADRS-10 Total Score | -7.8 units on a scale | Standard Deviation 8.5 |
| Naltrexone | Change in MADRS-10 Total Score | -18.2 units on a scale | Standard Deviation 5.5 |
Secondary
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
Population: Study completers.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in MADRS-15 Total Score | -10.7 units on a scale | Standard Deviation 10 |
| Naltrexone | Change in MADRS-15 Total Score | -23.4 units on a scale | Standard Deviation 6.8 |
Secondary
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
Population: Study completers.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Final CGI-I Score | 3.5 units on a scale | Standard Deviation 0.8 |
| Naltrexone | Final CGI-I Score | 2.2 units on a scale | Standard Deviation 1.2 |
Secondary
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.
Population: Study completers.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Remission Rate | 0 Participants |
| Naltrexone | Remission Rate | 3 Participants |
Secondary
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
Population: Study completers.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Response Rate | 1 Participants |
| Naltrexone | Response Rate | 3 Participants |
Comparison: Response rates were based on attaining a reduction in the HAM-D-17 scale of 50% or greater compared to baseline. We hypothesized that naltrexone would produce a significantly greater response rate than placebo.p-value: 0.55Chi-squared