Palmitoylethanolamide as adjunctive therapy in major depressive disorder: A double-blind, randomized and placebo-controlled trial

Background: Experimental studies provide evidence for antidepressant effects of Palmitoylethanolamide (PEA) in animal models of depression. We aimed to evaluate the efficacy and tolerability of PEA add-on therapy in treatment of patients with major depressive disorder (MDD). Methods: In a randomized double-blind, and placebo-controlled study, 58 patients with MDD (DSM-5) and Hamilton Depression Rating Scale (HAM-D) score >= 19 were randomized to receive either 600 mg twice daily Palmitoylethanolamide or placebo in addition to citalopram for six weeks. Patients were assessed using the HAM-D scale at baseline and weeks 2, 4, and 6. Results: Fifty-four individuals completed the trial. At week 2, patients in the PEA group demonstrated significantly greater reduction in HAM-D scores compared to the placebo group (8.30 +/- 2.41 vs. 5.81 +/- 3.57, P =.004). The PEA group also demonstrated significantly greater improvement in depressive symptoms [F (3, 156) = 3.35, P =.021] compared to the placebo group throughout the trial period. The patients in the PEA group experienced more response rate (>= 50% reduction in the HAM-D score) than the placebo group (100% vs. 74% respectively, P =.01) at the end of the trial. Baseline parameters and frequency of side effects were not significantly different between the two groups. Limitations: The population size in this study was small and the follow-up period was relatively short. Conclusions: Palmitoylethanolamide adjunctive therapy to citalopram can effectively improve symptoms of patients (predominantly male gender) with major depressive disorder. PEA showed rapid-onset antidepressant effects which need further investigation.