Low-Dose Naltrexone (LDN) for Depression Relapse and Recurrence
Condition: Major Depressive Disorder; Depression, Unipolar; Recurrence; Relapse
MeSH terms: Recurrence; Depression; Depressive Disorder; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 2

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).
    

Intervention name(s): Naltrexone; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 1 mg of naltrexone will be given twice daily to all patients assigned to active drug.; Placebo identical in appearance to naltrexone will be given twice daily to all patients assigned to placebo.
Other intervention name(s): LDN
Intervention MeSH terms: Naltrexone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Depression; Recurrence; Relapse; Antidepressants; Naltrexone; Drug augmentation