Low-Dose Naltrexone (LDN) for Depression Relapse and Recurrence

Randomized, Proof-Of-Concept Trial of Augmentation of Antidepressants by Low Dose Naltrexone (LDN) for Patients With Breakthrough Symptoms of Major Depressive Disorder on Antidepressant Therapy

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.

Study Overview

• Status: Completed
• Conditions: Recurrence; Major Depressive Disorder; Depression, Unipolar; Relapse
• Intervention / Treatment: Drug: Placebo; Drug: Naltrexone

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).

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital; Depression Research and Clinical Program

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; In this arm, patients will receive placebo for three weeks.	Drug: Placebo; Placebo identical in appearance to naltrexone will be given twice daily to all patients assigned to placebo.
Experimental: Naltrexone; 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.; Other Names: LDN

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Change from baseline to week 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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.	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.	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.	Remission rate at 3 weeks.

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: Boston Clinical Trials (BCT)
• Investigators: Principal Investigator: David Mischoulon, M.D., Massachusetts General Hospital

Publications and helpful links

General Publications

• Mischoulon D, Hylek L, Yeung AS, Clain AJ, Baer L, Cusin C, Ionescu DF, Alpert JE, Soskin DP, Fava M. Randomized, proof-of-concept trial of low dose naltrexone for patients with breakthrough symptoms of major depressive disorder on antidepressants. J Affect Disord. 2017 Jan 15;208:6-14. doi: 10.1016/j.jad.2016.08.029. Epub 2016 Oct 1. Erratum In: J Affect Disord. 2017 Oct 27;227:198.

Study record dates

Study Major Dates

• Study Start: June 1, 2013
• Primary Completion (Actual): June 1, 2015
• Study Completion (Actual): June 1, 2015

Study Registration Dates

• First Submitted: May 20, 2013
• First Submitted That Met QC Criteria: June 10, 2013
• First Posted (Estimate): June 11, 2013

Study Record Updates

• Last Update Posted (Actual): February 24, 2017
• Last Update Submitted That Met QC Criteria: January 5, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: Depression; Recurrence; Naltrexone; Relapse; Antidepressants; Drug augmentation
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Pathologic Processes; Mood Disorders; Disease Attributes; Depression; Depressive Disorder; Recurrence; Depressive Disorder, Major; Physiological Effects of Drugs; Peripheral Nervous System Agents; Sensory System Agents; Narcotic Antagonists; Alcohol Deterrents; Naltrexone
• Other Study ID Numbers: 2013P000371

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No