Add-on Therapy with Melatonin in the Acute Bipolar Mania Treatment: Results of a Randomized, Placebo-controlled Trial

Background and Objective: Prior research indicates that disruptions in melatonin secretion levels and timing could be linked to the pathophysiology of bipolar disorder. Our study aimed to assess the effectiveness of melatonin as an adjunctive therapy to classical mood stabilizers in addressing sleep impairment and mood symptoms in bipolar patients currently experiencing manic episodes. Methods: Fifty-eight hospitalized patients, with a mean age of 38.04 +/- 11.03, experiencing an acute manic episode and receiving valproate sodium treatment for one week were randomly assigned to either the melatonin group or the placebo group. Both melatonin and a matched placebo were initiated at a dosage of 3 mg/day at bedtime for the first week and increased to 6 mg/day for the subsequent three weeks. The primary efficacy endpoint focused on evaluating the severity of manic symptoms using the Young Mania Rating Scale (YMRS) at enrollment and at weeks 1, 2, and 4 post-interventions. Additionally, as a secondary efficacy endpoint, the change in insomnia severity was assessed at the end of the study period using the Insomnia Severity Index (ISI) questionnaire. Results: Analyses were conducted on an Intention-to-Treat (ITT) analysis dataset. Despite a significant decrease in mean Young Mania Rating Scale (YMRS) scores over the four-week study period in both treatment groups, melatonin exhibited a notably higher improvement in manic symptoms compared to the placebo (p-value <= 0.001). By the end of week 4, patients receiving a placebo demonstrated a mean +/- SD decrease in YMRS scores of -17.3 +/- 4.75, while those treated with melatonin experienced a significantly more reduction, with a mean +/- SD of -21.06 +/- 5.92 (p-value = 0.012). The proportion of responders, defined as patients with a >= 50% reduction in YMRS total score, and remitters, defined as those with an endpoint YMRS score <= 12, was also significantly higher in the melatonin-treated group compared to the placebo group. Furthermore, at the study endpoint, the melatonin group experienced a greater reduction in the mean ISI score compared to the placebo group (11.51 +/- 3.07 versus 8.97 +/- 3.56; p-value < 0.001). Importantly, melatonin was well tolerated by the study patients at this dosage. Conclusion: In summary, our study findings provide support for the use of melatonin as an adjunctive therapy in the treatment of acute bipolar mania. The positive outcomes observed warrant further investigations to replicate and extend these findings, contributing to a more comprehensive understanding of melatonin's role in managing bipolar disorder during manic episodes.