Randomized, Proof-Of-Concept Trial of Low Dose Naltrexone for Patients with Breakthrough Symptoms of Major Depressive Disorder on Antidepressants

Abstract Background Given the proposed dopaminergic mechanism of low-dose naltrexone (LDN), we examined its efficacy as augmentation for depressive breakthrough on pro-dopaminergic antidepressant regimens. Methods 12 adults (67% female, mean age = 45 ± 12) with recurrent DSM-IV major depressive disorder (MDD) on dopaminergic antidepressant regimens (stimulants, dopamine agonists, bupropion [≥300 mg/day], aripiprazole [≤2.5 mg/day], or sertraline [≥150 mg/day]) were randomized to naltrexone 1 mg b.i.d. (n=6) or placebo (n=6) augmentation for 3 weeks. Results All subjects completed the trial. Hamilton Depression Rating Scale (HAMD-17) scores (primary outcome measure) decreased from 21.2 ± 2.0 to 11.7 ± 7.7 for LDN, from 23.7 ± 2.3 to 17.8 ± 5.9 for placebo (Cohen's d=0.62; p=0.3 between treatment groups). HAMD-28 scores decreased from 26.2 ± 4.0 to 12.0 ± 9.8 for LDN, from 26.3 ± 2.6 to 19.8 ± 6.6 for placebo (d=1.15; p=0.097). Montgomery-Asberg Depression Rating Scale (MADRS-10 item) scores decreased from 30.4 ± 4.9 to 12.2 ± 8.4 for LDN, from 30.7 ± 4.3 to 22.8 ± 8.5) for placebo (d=1.45; p=0.035). MADRS-15 item scores decreased from 36.6 ± 6.2 to 13.2 ± 8.8 for LDN, from 36.7 ± 4.2 to 26.0 ±10.0 for placebo (d=1.49; p=0.035). Clinical Global Improvement Scale-Severity (CGI-S) scores decreased from 4.3 ± 0.5 to 3.0 ± 1.1 for LDN, from 4.3 ± 0.5 to 4.0 ± 0.6 for placebo (d=1.22; p=0.064). Limitations Small study; restrictions on allowed antidepressants. Conclusion LDN augmentation showed some benefit for MDD relapse on dopaminergic agents. Confirmation in larger studies is needed.